Magnetic Resonance Force Microscopy with a One-Dimensional Resolution of 0.9 Nanometers.

Magnetic resonance force microscopy (MRFM) is a scanning probe technique capable of detecting MRI signals from nanoscale sample volumes, providing a paradigm-changing potential for structural biology and medical research. Thus far, however, experiments have not reached sufficient spatial resolution for retrieving meaningful structural information from samples. In this work, we report MRFM imaging scans demonstrating a resolution of 0.9 nm and a localization precision of 0.6 nm in one dimension. Our progress is enabled by an improved spin excitation protocol furnishing us with sharp spatial control on the MRFM imaging slice, combined with overall advances in instrument stability. From a modeling of the slice function, we expect that our arrangement supports spatial resolutions down to 0.3 nm given sufficient signal-to-noise ratio. Our experiment demonstrates the feasibility of subnanometer MRI and realizes an important milestone toward the three-dimensional imaging of macromolecular structures.

Nanoladder Cantilevers Made from Diamond and Silicon.

We present a "nanoladder" geometry that minimizes the mechanical dissipation of ultrasensitive cantilevers. A nanoladder cantilever consists of a lithographically patterned scaffold of rails and rungs with feature size ∼100 nm. Compared to a rectangular beam of the same dimensions, the mass and spring constant of a nanoladder are each reduced by roughly 2 orders of magnitude. We demonstrate a low force noise of 158-42+62 zN and 190-33+42 zN in a 1 Hz bandwidth for devices made from silicon and diamond, respectively, measured at temperatures between 100-150 mK. As opposed to bottom-up mechanical resonators like nanowires or nanotubes, nanoladder cantilevers can be batch-fabricated using standard lithography, which is a critical factor for applications in scanning force microscopy.

Nanoscale Imaging of Current Density with a Single-Spin Magnetometer.

Charge transport in nanostructures and thin films is fundamental to many phenomena and processes in science and technology, ranging from quantum effects and electronic correlations in mesoscopic physics, to integrated charge- or spin-based electronic circuits, to photoactive layers in energy research. Direct visualization of the charge flow in such structures is challenging due to their nanometer size and the itinerant nature of currents. In this work, we demonstrate noninvasive magnetic imaging of current density in two-dimensional conductor networks including metallic nanowires and carbon nanotubes. Our sensor is the electronic spin of a diamond nitrogen-vacancy center attached to a scanning tip and operated under ambient conditions. Using a differential measurement technique, we detect DC currents down to a few µA with a current density noise floor of ∼2 × 104 A/cm2. Reconstructed images have a spatial resolution of typically 50 nm, with a best-effort value of 22 nm. Current density imaging offers a new route for studying electronic transport and conductance variations in two-dimensional materials and devices, with many exciting applications in condensed matter physics and materials science.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

Atomic monolayer deposition on the surface of nanotube mechanical resonators.

We study monolayers of noble gas atoms (Xe, Kr, Ar, and Ne) deposited on individual ultraclean suspended nanotubes. For this, we record the resonance frequency of the mechanical motion of the nanotube, since it provides a direct measure of the coverage. The latter is the number of adsorbed atoms divided by the number of the carbon atoms of the suspended nanotube. Monolayers form when the temperature is lowered in a constant pressure of noble gas atoms. The coverage of Xe monolayers remains constant at 1/6 over a large temperature range. This finding reveals that Xe monolayers are solid phases with a triangular atomic arrangement, and are commensurate with the underlying carbon nanotube. By comparing our measurements to theoretical calculations, we identify the phases of Ar and Ne monolayers as fluids, and we tentatively describe Kr monolayers as solid phases. These results underscore that mechanical resonators made from single nanotubes are excellent probes for surface science.

High-altitude glacier archives lost due to climate change-related melting.

Global warming has caused widespread surface lowering of mountain glaciers. By comparing two firn cores collected in 2018 and 2020 from Corbassière glacier in Switzerland, we demonstrate how vulnerable these precious archives of past environmental conditions have become. Within two years, the soluble impurity records were destroyed by melting. The glacier is now irrevocably lost as an archive for reconstructing major atmospheric aerosol components.

Strong coupling between mechanical modes in a nanotube resonator.

We report on the nonlinear coupling between the mechanical modes of a nanotube resonator. The coupling is revealed in a pump-probe experiment where a mode driven by a pump force is shown to modify the motion of a second mode measured with a probe force. In a second series of experiments, we actuate the resonator with only one oscillating force. Mechanical resonances feature exotic line shapes with reproducible dips, peaks, and jumps when the measured mode is commensurate with another mode with a frequency ratio of either 2 or 3. Conventional line shapes are recovered by detuning the frequency ratio using the voltage on a nearby gate electrode. The exotic line shapes are attributed to strong coupling between the mechanical modes. The possibility to control the strength of the coupling with the gate voltage holds promise for various experiments, such as quantum manipulation, mechanical signal processing, and the study of the quantum-to-classical transition.

Gate-tunable split Kondo effect in a carbon nanotube quantum dot.

We show a detailed investigation of the split Kondo effect in a carbon nanotube quantum dot with multiple gate electrodes. Two conductance peaks, observed at finite bias in nonlinear transport measurements, are found to approach each other for increasing magnetic field, to result in a recovered zero bias Kondo resonance at finite magnetic field. Surprisingly, in the same charge state, but under different gate configurations, the splitting does not disappear for any value of the magnetic field, but we observe an avoided crossing. We think that our observations can be understood in terms of a two-impurity Kondo effect with two spins coupled antiferromagnetically. The exchange coupling between the two spins can be influenced by a local gate, and the non-recovery of the Kondo resonance for certain gate configurations is explained by the existence of a small antisymmetric contribution to the exchange interaction between the two spins.

Interchangeability of stress and amphetamine in sensitization.

In view of similarities between the behavioral, biochemical, and electrophysiological effects of amphetamine and stress, we tested the hypothesis that presentation of a stressor, mild tail pressure, can sensitize an animal to the later effects of amphetamine, and vice versa. Our findings supported this hypothesis and suggest that amphetamine and at least some stressors may be interchangeable in their ability to induce a sensitization. The data raise the possibility that stress might be a common variable contributing to both amphetamine psychosis and some forms of schizophrenia.

Gate-controlled phase switching in a parametron.

The parametron, a resonator-based logic device, is a promising physical platform for emerging computational paradigms. When the parametron is subject to both parametric pumping and external driving, complex phenomena arise that can be harvested for applications. In this paper, we experimentally demonstrate deterministic phase switching of a parametron by applying frequency tuning pulses. To our surprise, we find different regimes of phase switching due to the interplay between a parametric pump and an external drive. We provide full modeling of our device with numerical simulations and find excellent agreement between model and measurements. Our result opens up new possibilities for fast and robust logic operations within large-scale parametron architectures.

Ice-core evidence of earliest extensive copper metallurgy in the Andes 2700 years ago.

The importance of metallurgy for social and economic development is indisputable. Although copper (Cu) was essential for the wealth of pre- and post-colonial societies in the Andes, the onset of extensive Cu metallurgy in South America is still debated. Comprehensive archaeological findings point to first sophisticated Cu metallurgy during the Moche culture ~200-800 AD, whereas peat-bog records from southern South America suggest earliest pollution potentially from Cu smelting as far back as ~2000 BC. Here we present a 6500-years Cu emission history for the Andean Altiplano, based on ice-core records from Illimani glacier in Bolivia, providing the first complete history of large-scale Cu smelting activities in South America. We find earliest anthropogenic Cu pollution during the Early Horizon period ~700-50 BC, and attribute the onset of intensified Cu smelting in South America to the activities of the central Andean Chiripa and Chavin cultures ~2700 years ago. This study provides for the first time substantial evidence for extensive Cu metallurgy already during these early cultures.

Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression.

Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.

Ultrasensitive mechanical detection of magnetic moment using a commercial disk drive write head.

Sensitive detection of weak magnetic moments is an essential capability in many areas of nanoscale science and technology, including nanomagnetism, quantum readout of spins and nanoscale magnetic resonance imaging. Here we show that the write head of a commercial hard drive may enable significant advances in nanoscale spin detection. By approaching a sharp diamond tip to within 5 nm from a write pole and measuring the induced diamagnetic moment with a nanomechanical force transducer, we demonstrate a spin sensitivity of 0.032 µB Hz(-1/2), equivalent to 21 proton magnetic moments. The high sensitivity is enabled in part by the pole's strong magnetic gradient of up to 28 × 10(6) T m(-1) and in part by the absence of non-contact friction due to the extremely flat writer surface. In addition, we demonstrate quantitative imaging of the pole field with ∼10 nm spatial resolution. We foresee diverse applications for write heads in experimental condensed matter physics, especially in spintronics, ultrafast spin manipulation and mesoscopic physics.

Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension.

BACKGROUND: The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown. METHODS AND RESULTS: In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54+/-2.3 mm Hg, pulmonary vascular resistance (PVR) 1061+/-141 dyn x sec x cm(-5)). There was a significant transpulmonary gradient for big ET-1 with 31% +/-11% higher concentrations in the radial artery than in the pulmonary artery (P<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31+/-0.11 to 0.92+/-0.06 (P<0.007) was observed. The pulmonary net release of 3.10+/-0.65 pmol/min big ET-1 at baseline decreased to -1.24+/-1.32 pmol/min (P=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment. CONCLUSION: An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.

Analysis of sensitivity and specificity of cytokeratin 19 reverse transcriptase/polymerase chain reaction for detection of occult breast cancer in bone marrow and leukapheresis products.

PURPOSE: The work aimed to evaluate the sensitivity and specificity of the cytokeratin (CK) 19 reverse transcriptase/polymerase chain reaction (RT-PCR) for the detection of occult breast cancer in bone marrow and leukapheresis products. MATERIALS AND METHODS: Peripheral blood and bone marrow samples, obtained from 96 and 8 healthy donors respectively, served as negative controls. A total of 115 bone marrow samples and 29 leukapheresis samples from routine patients with breast cancer were analysed by CK19 RT-PCR. The PCR results were compared with those from routine immunocytology for CK8, 18, 19. RESULTS: The CK19 RT-PCR technique with primer pairs from Datta et al. (J Clin Oncol 12: 475-482, 1994), using an annealing temperature of 72 degrees C, allowed the detection of one tumour cell in 10(7) mononuclear cells. None of the control samples (96 peripheral blood and 8 bone marrow) that were positive for beta2-microglobulin by RT-PCR showed a signal for CK19. However, expression of CK19 mRNA was observed in 40.87% (70/115) of bone marrow and in 24.13% (7/29) of leukapheresis samples of patients with breast cancer. Standard immunocytology and PCR were combined for the detection of tumour cells. Five of the 65 bone marrow samples were found to be positive by CK19 RT-PCR, but were negative with the immunocytology method. CONCLUSION: RT-PCR using CK19-specific primers and optimal experimental conditions is a reliable and specific method for the detection of micrometastatic breast cancer cells.

Evaluation of the reverse transcriptase/polymerase chain reaction for carcinoembryonic antigen for the detection of breast cancer dissemination in bone marrow and peripheral blood.

This study evaluated the specificity and sensitivity of the reverse transcriptase/polymerase chain reaction (RT-PCR) for carcinoembryonic antigen (CEA) for identification of breast tumour cells in bone marrow and in peripheral blood. Using one primer set from the A2/B3 domains of CEA with five to seven mismatches to other CEA-family members allowed reproducible detection of 1 colon tumour cell and 10 breast tumour cells in 10(7) mononuclear cells. Bone marrow samples from 181 patients with breast cancer were analysed by CEA-RT-PCR; 50 of these samples were analysed in parallel by routine immunocytochemistry. CEA-mRNA-positive bone marrow cells were found in 27.6% of the patients (50/181) with breast cancer. Five immunocytochemistry-positive samples were negative when analysed by CEA-RT-PCR. Limiting factors in the detection of micrometastatic breast tumour cells by CEA-RT-PCR are the heterogeneity of the tumour cells and the deficient expression of CEA in some of these cells. However, CEA-RT-PCR using the specific primer could detect 1 colon tumour cell in 1 x 10(7) normal peripheral blood mononuclear cells.

Sensitive detection of micrometastases in bone marrow from patients with breast cancer using immunomagnetic isolation of tumor cells in combination with reverse transcriptase/polymerase chain reaction for cytokeratin-19.

We report a highly sensitive method to detect rare human breast cancer cells, which combines an immunomagnetic separation (IMS) using antibody BM2 against MUC-1 with cytokeratin-19 (CK19) and the reverse transcriptase/polymerase chain reaction (RT-PCR). The IMS-RT-PCR technique allows the detection of 1 tumor cell/10(7)-10(8) mononuclear cells. This is at least ten times more sensitive than CK19 RT-PCR alone, or immunocytochemistry. All 117 peripheral blood and 8 bone marrow samples obtained from healthy donors as negative controls were positive for beta2-microglobulin by RT-PCR but negative for CK19 by IMS-RT-PCR or RT-PCR alone. Out of 26 bone marrow samples from breast cancer patients, 18 had CK19 transcripts detectable by IMS-RT-PCR. In contrast, only 14 and 13 samples from the 26 were found to be positive by RT-PCR alone or by routine immunocytochemical staining. In conclusion, IMS-RT-PCR for CK19 is a highly sensitive and specific method for detecting very low numbers of micrometastatic breast cancer cells in bone marrow amidst an excess of nonmalignant cells. For the early diagnosis of disseminating disease, this assay is more efficient than RT-PCR alone and routine immunocytochemistry.

Amphetamine stereotypy is not a homogeneous phenomenon: sniffing and licking show distinct profiles of sensitization and tolerance.

Sniffing and licking components of amphetamine-induced stereotypy were studied separately during chronic drug treatment. Sniffing showed a gradual increase, or sensitization, in intensity and duration. By contrast, licking developed tolerance for approximately the first 21 days, followed by a progressive increase. Stereotypy is therefore not a homogeneous phenomenon, and sniffing and licking are probably subserved by distinct neuroanatomic substrates. The sensitization of sniffing behavior may be related to the induction of amphetamine-induced paranoid psychosis in humans.

Venom of a parasitoid wasp induces prolonged grooming in the cockroach

The parasitoid wasp Ampulex compressa hunts cockroaches Periplaneta americana, stinging them first in the thorax and then in the head, the sting penetrating towards the subesophageal ganglion. After being stung the cockroach grooms almost continuously for approximately 30 min, performing all the normal components of grooming behavior. This excessive grooming is only seen after the head sting and cannot be attributed to stress, to contamination of the body surface or to systemic or peripheral effects. This suggests that the venom is activating a neural network for grooming. We suggest that the venom induces prolonged grooming by stimulating dopamine receptors in the cockroach, for the following reasons. (1) Reserpine, which causes massive release of monoamines, induces excessive grooming. (2) Dopamine injected into the hemocoel also induces excessive grooming and is significantly more effective than octopamine or serotonin. In addition, the dopamine agonist SKF 82958 induces excessive grooming when injected directly into the subesophageal ganglion. (3) Injection of the dopamine antagonist flupenthixol greatly reduces venom-induced grooming. (4) Dopamine, or a dopamine-like substance, is present in the venom.

Detection of central pulmonary artery thromboemboli by transesophageal echocardiography in patients with severe pulmonary embolism.

Transthoracic echocardiography generally provides only indirect signs of pulmonary embolism. In contrast, with transesophageal echocardiography the thromboembolus itself can be visualized in the central parts of the pulmonary artery. The aims of our study were to evaluate, first, the incidence of central pulmonary artery thromboemboli in patients with severe pulmonary embolism, and second, the accuracy of the echocardiographic diagnosis. Our study group comprised 60 patients with proved severe pulmonary embolism. All patients were examined by transthoracic and transesophageal echocardiography. The echocardiographic findings concerning the absence or presence of central pulmonary artery thromboemboli were compared with the results of different reference methods. Central pulmonary thromboemboli were found in 35 patients (58.3%) by echocardiography. Two types of thrombus were differentiated. Type A is a long, highly mobile thrombus, and type B is an immobile wall-adherent thrombus. In comparison with the reference methods, we determined a sensitivity of 96.7% and a specificity of 88% for the echocardiographic detection of central pulmonary artery thromboemboli in patients with severe pulmonary embolism. Transesophageal echocardiography seems to be a useful method for the diagnosis of severe pulmonary embolism. In our series, central pulmonary artery thromboemboli were present in more than half of the patients. In these cases, transesophageal echocardiography can clarify the diagnosis within a few minutes without further invasive diagnostic procedures.