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Femtosecond X-ray laser pulses are used to probe the structure of liquid water in micrometre-sized droplets that have been cooled below the homogeneous ice nucleation temperature, revealing the existence of metastable bulk liquid water down to temperatures of 227 kelvin. Anomalous bevaviour of supercooled water Water's anomalous physical properties become markedly enhanced upon supercooling below the freezing point and even seem to diverge towards infinity at around 228 K. Two papers in this issue use contrasting techniques to study this little-explored 'no-man's land' of water where extremely fast ice formation has prohibited measurements of the liquid state. Jonas Sellberg et al . use femtosecond X-ray laser pulses to measure bulk liquid water structure in droplets evaporatively cooled to 227 K. Even at this temperature some droplets remained liquid on a millisecond timescale. Pushing this technique further can shed light on controversial scenarios that aim to describe and explain the many anomalous properties of water. Jeremy Palmer et al . use six advanced computational methods to demonstrate the existence of two metastable liquid phases of ST2 water at the same deeply supercooled condition, undergoing a liquid–liquid transition that meets stringent thermodynamic criteria and could explain the behavior of water in this regime. Water has a number of anomalous physical properties, and some of these become drastically enhanced on supercooling below the freezing point. Particular interest has focused on thermodynamic response functions that can be described using a normal component and an anomalous component that seems to diverge at about 228 kelvin (refs 1 , 2 , 3 ). This has prompted debate about conflicting theories 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 that aim to explain many of the anomalous thermodynamic properties of water. One popular theory attributes the divergence to a phase transition between two forms of liquid water occurring in the ‘no man’s land’ that lies below the homogeneous ice nucleation temperature ( T H ) at approximately 232 kelvin 13 and above about 160 kelvin 14 , and where rapid ice crystallization has prevented any measurements of the bulk liquid phase. In fact, the reliable determination of the structure of liquid water typically requires temperatures above about 250 kelvin 2 , 15 . Water crystallization has been inhibited by using nanoconfinement 16 , nanodroplets 17 and association with biomolecules 16 to give liquid samples at temperatures below T H , but such measurements rely on nanoscopic volumes of water where the interaction with the confining surfaces makes the relevance to bulk water unclear 18 . Here we demonstrate that femtosecond X-ray laser pulses can be used to probe the structure of liquid water in micrometre-sized droplets that have been evaporatively cooled 19 , 20 , 21 below T H . We find experimental evidence for the existence of metastable bulk liquid water down to temperatures of  kelvin in the previously largely unexplored no man’s land. We observe a continuous and accelerating increase in structural ordering on supercooling to approximately 229 kelvin, where the number of droplets containing ice crystals increases rapidly. But a few droplets remain liquid for about a millisecond even at this temperature. The hope now is that these observations and our detailed structural data will help identify those theories that best describe and explain the behaviour of water.

Light–matter interactions are ubiquitous, and underpin a wide range of basic research fields and applied technologies. Although optical interactions have been intensively studied, their microscopic details are often poorly understood and have so far not been directly measurable. X-ray and optical wave mixing was proposed nearly half a century ago as an atomic-scale probe of optical interactions but has not yet been observed owing to a lack of sufficiently intense X-ray sources. Here we use an X-ray laser to demonstrate X-ray and optical sum-frequency generation. The underlying nonlinearity is a reciprocal-space probe of the optically induced charges and associated microscopic fields that arise in an illuminated material. To within the experimental errors, the measured efficiency is consistent with first-principles calculations of microscopic optical polarization in diamond. The ability to probe optical interactions on the atomic scale offers new opportunities in both basic and applied areas of science. A free-electron laser provides a sufficiently intense source of X-rays to allow X-ray and optical wave mixing, here demonstrated by measuring the induced charge density and associated microscopic fields in single-crystal diamond. Now X-rays and light do mix Interactions between light and matter are central to many areas of science, but the microscopic details of how light can change matter remain unclear because of observational difficulties. These details can be probed by mixing X-rays and optical waves, an X-ray-scattering process that was proposed nearly half a century ago, but was beyond the technology of the time. Now, with the advent of free-electron lasers, X-rays of sufficient intensity have become available. In this week's Nature , Ernie Glover et al ., working with the Linac Coherent Light Source, report X-ray and optical mixing (or sum-frequency generation) in diamond. The new capability may enable direct visualization of the making and breaking of chemical bonds.

We describe the design and operation of a transmissive single-shot spectrometer for the measurement of hard x-ray free electron laser (FEL) source spectrum at the Linac Coherent Light Source (LCLS). The spectrometer was built around a 10 μm thick near-perfect silicon single crystal that was cylindrically bent. Its energy range covered the full FEL bandwidth while its resolution was sufficient for resolving single spectral spikes characteristics of the FELs. Its application will not only greatly facilitate the understanding and optimization of the x-ray FEL sources, but can also serve as an invaluable inline diagnostic tool for experiments where the spectral content of the source plays an important role in data interpretation.

Auto-tuned induction coil technology, based upon phase-locked loop circuitry (PLL), was developed and shown to be an effective tool for in-vivo measurement of electrical conductivity of human tissues. Because electrical contact is not required, several disadvantages of the electrode method for conductivity determination are avoided, such as electrode polarization and variable conductivity associated with the stratum corneum of the epidermis. Fixed frequency excitation is supplied to a parallel tuned RLC circuit, or \"sensor\", while bias applied to a varactor diode is automatically adjusted via PLL circuitry to maintain the RLC sensor at resonance. Since resonant impedance of a coil positioned near a conductive object is known to be frequency dependent, such an arrangement permits precise calibration of the sensor against a set of standard Potassium Chloride solutions. In our experiments, a two-layer spiral coil is used with upper and lower spiral arms staggered so as to reduce inter-winding coil capacitance. Preliminary in-vivo testing was done on the forearms of a single male subject as a prelude to more extensive use in a clinical setting. In that instance, electrical conductivity at the proximal volar forearm location was shown to depend on forearm elevation. Clinical studies using our prototype, as well as further consideration of the \"elevation effect\", are discussed in a companion paper.

Two clinical studies were completed using an auto-tuned induction coil conductivity sensor (ICCS) to determine the effects of a variety of factors on the electrical conductivity of soft tissue. In addition to fifteen \"subject variables\" such as blood pressure and others, we have specifically focused on considering the role of such factors as gender, age, BMI, smoking and elevation of extremities. Measurements were made at seven sites on either side of the body for a total of fourteen. Higher conductivities were obtained for women than men at all sites. At five sites, where age was a significant factor, conductivity was found to decline with increased age. Interestingly, smokers as a group tended to have reduced conductivity, suggesting that aging and smoking have similar effects on the microvasculature of soft tissue. Generally speaking, electrical conductivity is observed to increase in response to increased elevation at sites located on extremities. Considering just healthy adults, a definite pattern of elevation-induced electrical conductivity displacement emerges when subjects are flagged according to high, low or moderate blood pressure. We suggest that violations of this pattern may provide a method for identifying those individuals in an early stage of peripheral vascular disease.

The successful lasing and operation of the LCLS hard X-ray FEL has brought tremendous interest to the user community spanning a wide range of scientific disciplines including physics, chemistry, structural biology, and material science. It created demand on beam time that is often left unfulfilled. Here we report experimental measurements of ultra-thin silicon single-crystal membranes for potentially beam-sharing the LCLS beam. The samples included the (111), (220), and (400) orientations with thicknesses ranging from 5 to 20 μm. Both high-resolution rocking curves and topographic data were first obtained using synchrotron X-rays, demonstrating near ideal diffraction qualities. Subsequent tests using the full LCLS beam revealed lattice distortions from beam-induced membrane vibrations, which were shown to be effectively reduced by ambient air and smaller membrane dimensions. High diffraction quality thin-diamonds in the (111) orientation are also being pursued as a parallel effort. Both approaches are paving a way for a practical beam-sharing implementation at LCLS in the near future.

Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. B A Kallmann , M Hüther , M Tubes , J Feldkamp , J Bertrams , F A Gries , E F Lampeter and H Kolb Clinical Department of the Diabetes Research Institute, Heinrich-Heine-University of Dusseldorf, Germany. Abstract Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.

In a randomized study, prevention of goiter recurrence with l‐thyroxine was compared with pure iodide substitution after thyroid surgery for nodular goiter in an iodine‐deficient area. Altogether 107 patients were followed up for 52 weeks after thyroid resection. The thyroid volume was determined sonographically. Free thyroxine, total thyroxine, thyrotropin, thyroglobulin, and antibodies to thyroglobulin and thyroid peroxidase were measured. The thyroid volume decreased slightly over the course of a year in the two therapy groups. There was no significant difference between the two groups. Recurrences were seen with both l‐thyroxine medication and iodide substitution. The thyroglobulin levels fell significantly over the 52‐week follow‐up period in the iodide group. Antibody formation was not observed under iodine substitution. In an area of iodine deficiency, substitution with iodide is just as effective as medicating the patients with l‐thyroxine for preventing recurrences.

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Thl cytokines γ-interferon (IFN-γ) (P = 0.028) and tumor necrosis factor α (TNF-α) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Thl and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Thl or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-α and IL-4 than normal subjects (P = 0.001–0.006). However, when the balance between Thl and Th2 cytokine production was analyzed in individuals, the ratio between IFN-γ or TNF-α and IL-4 or IL-10 was clearly biased toward Thl reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Thl) in IDDM or humoral immunity (Th2) in Graves' disease.