Probable heat capacity signature of the supersolid transition.

Liquid 4He enters the superfluid state and flows without friction below 2.176 K. Thin liquid films adsorbed on solid substrates undergo the same transformation, although at a lower temperature. When the substrate is subjected to oscillatory motion a portion of the film, known as the superfluid fraction, decouples from the oscillation. A similar phenomenon has been observed in solid 4He, in which a fraction of the solid seems to decouple from the motion of the surrounding lattice. Although this observation has been replicated in various laboratories, no thermodynamic signature of the possible supersolid transition has been seen. Here we report the finding of a heat capacity peak that coincides with the onset of mass decoupling. This complementary experimental evidence supports the existence of a genuine transition between the normal solid and supersolid phases of 4He.

Development of a dosimeter prototype with machine learning based 3-D dose reconstruction capabilities.

A 3-D dosimeter fills the need for treatment plan and delivery verification required by every modern radiation-therapy method used today. This report summarizes a proof-of-concept study to develop a water-equivalent solid 3-D dosimeter that is based on novel radiation-hard scintillating material. The active material of the prototype dosimeter is a blend of radiation-hard peroxide-cured polysiloxane plastic doped with scintillating agent P-Terphenyl and wavelength-shifter BisMSB. The prototype detector was tested with 6 MV and 10 MV x-ray beams at Ohio State University's Comprehensive Cancer Center. A 3-D dose distribution was successfully reconstructed by a neural network specifically trained for this prototype. This report summarizes the material production procedure, the material's water equivalency investigation, the design of the prototype dosimeter and its beam tests, as well as the details of the utilized machine learning approach and the reconstructed 3-D dose distributions.

GroEL-mediated folding of structurally homologous dihydrofolate reductases.

Using stopped-flow fluorescence techniques, we have examined both the refolding and unfolding reactions of four structurally homologous dihydrofolate reductases (murine DHFR, wild-type E. coli DHFR, and two E. coli DHFR mutants) in the presence and absence of the molecular chaperonin GroEL. We show that GroEL binds the unfolded conformation of each DHFR with second order rate constants greater than 3 x 10(7) M(-1)s(-1) at 22 degrees C. Once bound to GroEL, the proteins refold with rate constants similar to those for folding in the absence of GroEL. The overall rate of formation of native enzyme is decreased by the stability of the complex between GroEL and the last folding intermediate. For wild-type E. coli DHFR, complex formation is transient while for the others, a stable complex is formed. The stable complexes are the same regardless of whether they are formed from the unfolded or folded DHFR. When complex formation is initiated from the native conformation, GroEL binds to a pre-existing non-native conformation, presumably a late folding intermediate, rather than to the native state, thus shifting the conformational equilibrium toward the non-native species by mass action. The model presented here for the interaction of these four proteins with GroEL quantitatively describes the difference between the formation of a transient complex and a stable complex as defined by the rate constants for release and rebinding to GroEL relative to the rate constant for the last folding step. Due to this kinetic partitioning, three different mechanisms can be proposed for the formation of stable complexes between GroEL and either murine DHFR or the two E. coli DHFR mutants. These data show that productive folding of GroEL-bound proteins can occur in the absence of nucleotides or the co-chaperonin GroES and suggest that transient complex formation may be the functional role of GroEL under normal conditions.

Native Escherichia coli and murine dihydrofolate reductases contain late-folding non-native structures.

We have examined the equilibrium and kinetic folding properties of two structurally homologous dihydrofolate reductases, Escherichia coli DHFR (EcDHFR) and murine DHFR (MuDHFR), as a function of temperature and ligand concentration. Conformational heterogeneity in native DHFR is well documented, and the results demonstrate that the non-native form(s) represents late intermediate(s) in the folding process. We have measured the concentrations of native and non-native forms and the rate constants for their interconversion over a temperature range of 3 degreesC to 49 degreesC, allowing characterization of the thermodynamic as well as the kinetic properties of the final folding step(s) relative to the overall folding reaction. Differences in ligand binding suggest that the intermediate structures for these two proteins may be different during refolding.

The chaperonin GroEL binds to late-folding non-native conformations present in native Escherichia coli and murine dihydrofolate reductases.

Dihydrofolate reductases from mouse (MuDHFR) or Escherichia coli (EcDHFR) are shown to refold via several intermediate forms, each of which can bind to the chaperonin GroEL. When stable complexes with GroEL are formed, they consist of late-folding intermediates. In addition, we find that late-folding intermediates that are present in the native enzyme bind to GroEL. For the E. coli and murine proteins, the extent of protein bound increases as the temperature is increased from 8 degreesC to 42 degreesC, at which temperature either protein is completely bound as the last (EcDHFR) or the last two (MuDHFR) folding intermediate(s). Thus for EcDHFR, the binding is transient at low temperature (<30 degreesC) and stable at high temperature (>35 degreesC). For MuDHFR, complex formation appears less temperature dependent. In general, the data demonstrate that the overall binding free energy for the interaction of GroEL with native DHFR is the sum of the free energy for the first step in DHFR unfolding, which is unfavorable, and the free energy of binding the non-native conformation, which is favorable. For EcDHFR, this results in an overall binding free energy that is unfavorable below 30 degreesC. Over the temperature range of 8 degreesC to 42 degreesC, GroEL binds MuDHFR more tightly than EcDHFR, due partially to a small free energy difference between two pre-existing non-native conformations of MuDHFR, resulting in binding to more than one folding intermediate.

Cooperative effects of potassium, magnesium, and magnesium-ADP on the release of Escherichia coli dihydrofolate reductase from the chaperonin GroEL.

Previous investigation has shown that at 22 degrees C and in the presence of the chaperonin GroEL, the slowest step in the refolding of Escherichia coli dihydrofolate reductase (EcDHFR) reflects release of a late folding intermediate from the cavity of GroEL (Clark AC, Frieden C, 1997, J Mol Biol 268:512-525). In this paper, we investigate the effects of potassium, magnesium, and MgADP on the release of the EcDHFR late folding intermediate from GroEL. The data demonstrate that GroEL consists of at least two conformational states, with apparent rate constants for EcDHFR release that differ by four- to fivefold. In the absence of potassium, magnesium, and ADP, approximately 80-90% of GroEL resides in the form with the faster rate of release. Magnesium and potassium both shift the distribution of GroEL forms toward the form with the slower release rate, though cooperativity for the magnesium-induced transition is observed only in the presence of potassium. MgADP at low concentrations (0-50 microM) shifts the distribution of GroEL forms toward the form with the faster release rate, and this effect is also potassium dependent. Nearly identical results were obtained with a GroEL mutant that forms only a single ring, demonstrating that these effects occur within a single toroid of GroEL. In the presence of saturating magnesium, potassium, and MgADP, the apparent rate constant for the release of EcDHFR from wild-type GroEL at 22 degrees C reaches a limiting value of 0.014 s(-1). For the single ring mutant of GroEL, the rate of EcDHFR release under the same conditions reaches a limiting value of 0.024 s(-1), suggesting that inter-ring negative cooperativity exists for MgADP-induced substrate release. The data suggest that MgADP preferentially binds to one conformation of GroEL, that with the faster apparent rate constant for EcDHFR release, and induces a conformational change leading to more rapid release of substrate protein.

Acute acquired comitant esotropia.

Acute acquired comitant esotropia has been used to describe a dramatic onset of a relatively large angle of esotropia with diplopia and minimal refractive error. We describe six children aged 5 to 11 years who developed an acute non-accommodative esotropia with diplopia. Neurological examination, including CT scan, in each of these children gave negative results. We suggest that this is an unusual presentation of esotropia of undetermined aetiology. The diagnosis, clinical characteristics, and management are discussed.

Bone loss during oestriol therapy in postmenopausal women.

In contrast to all other oestrogens examined thus far oestriol hemisuccinate (12 mg/day) did not prevent bone loss in 28 postmenopausal women. The average bone loss, however, was somewhat less than expected from placebo studies, while the bone loss achieved by a group taking 4-6 mg/day was equal to that achieved by previous placebo groups. To be an effective agent for prevention of post-menopausal osteoporosis oestriol would have to be prescribed in daily doses considerably in excess of 12 mg.

PIP: Studies have shown that estrogen therapy is useful in preventing bone loss, osteoporosis, in postmenopausal women. Long-term estrogen therapy, however, may be associated with an increased incidence of endometrial carcinoma. To be effective against bone loss, the therapy would have to be continued for a long time. A double-blind study was conducted to determine whether estriol, which has weaker effects on the endometrium, at relatively low doses could be used to retard osteoporosis in postmenopausal women. The estriol, at 4mg daily, was ineffective in controlling postmenopausal symptoms; 35% of the patients required a 14 mg-dose, and 5 patients were dissatisfied even with that doage. In addition, the 12 mg-dose did not prevent bone loss, which continued at a rate only slightly lower than for patients on placebo therapy. It is likely that a higher dosage would be more effective, but would cause the potential endometrial effects. Laboratory procedures involved in the study are outlined and results are graphed.

Evaluation of near-critical overdamping effects in slug-test response.

A slug test behaves as a harmonic oscillator, subject to both inertial effects and viscous damping. When viscous and inertial forces are closely balanced, the system is nearly critically damped, and water-level recovery is affected by inertial effects, but does not exhibit oscillation. These effects were investigated by use of type curves, generated both by modification of Kipp's (1985) computer program and by use of the Butler-Zhan (2004) model. Utility of the type curves was verified by re-analysis of the Regina slug test previously analyzed by Kipp. These type curves indicate that near-critical inertial effects result in early-time delayed water-level response followed by merger with, or more rapid recovery than, response for the fully damped case. Because of this early time response, slug tests in the moderately over-damped range are best analyzed using log-log type curves of (1 - H/H(0)) vs. Tt/r(2c). Failure to recognize inertial effects in slug test data could result in an over-estimate of transmissivity, and a too-small estimate of storage coefficient or too-large estimate of well skin. However, application of the widely used but highly empirical Hvorslev (1951) method to analyze both the Regina slug test and type-curve generated data indicate that such analyses provide T values within a factor of 2 of the true value.

Intracranial migration of Eucoleus (Capillaria) boehmi in a dog.

A 4-year-old, spayed-female great Dane was referred for surgical treatment of a suspected meningioma, diagnosed on magnetic resonance imaging 10 days prior to presentation. The suspected meningioma was removed via image-guided stereotactic craniotomy. Histopathological diagnosis was severe, locally extensive, chronic meningoencephalitis with an intralesional nematode egg. The egg was morphologically consistent with Eucoleus boehmi, and aberrant migration into the cranial cavity was the presumed cause of this lesion. Three faecal samples were collected and revealed 4+ E. boehmi eggs. Treatment involved 110 mg/kg fenbendazole (Panacur, Intervet) orally twice daily for 14 days. Nematodes including E. boehmi are a previously un-recognised source of intracranial disease in dogs, and should be considered as a differential for mass-like lesions visualised by magnetic resonance imaging.

Metallic Coulomb blockade thermometry down to 10 mK and below.

We present an improved nuclear refrigerator reaching 0.3 mK, aimed at microkelvin nanoelectronic experiments, and use it to investigate metallic Coulomb blockade thermometers (CBTs) with various resistances R. The high-R devices cool to slightly lower T, consistent with better isolation from the noise environment, and exhibit electron-phonon cooling [proportional] T(5) and a residual heat-leak of 40 aW. In contrast, the low-R CBTs display cooling with a clearly weaker T-dependence, deviating from the electron-phonon mechanism. The CBTs agree excellently with the refrigerator temperature above 20 mK and reach a minimum-T of 7.5 ± 0.2 mK.

Method for cooling nanostructures to microkelvin temperatures.

We propose a new scheme aimed at cooling nanostructures to microkelvin temperature based on the well established technique of adiabatic nuclear demagnetization: we attach each device measurement lead to an individual nuclear refrigerator, allowing efficient thermal contact to a microkelvin bath. On a prototype consisting of a parallel network of nuclear refrigerators, temperatures of ∼1 mK simultaneously on ten measurement leads have been reached upon demagnetization, thus completing the first steps toward ultracold nanostructures.

Heat capacity peak in solid 4He: effects of disorder and 3He impurities.

Heat capacity measurements with significantly improved resolution find the presence of a peak in a solid 4He sample in coexistence with liquid. With improved crystallinity, the peak decreases in height and moves to lower temperature. A hysteretic heat capacity signature consistent with 3He-4He phase separation, not detected in an earlier work is clearly observed.

Effect of 3He impurities on the nonclassical response to oscillation of solid 4He.

We have investigated the influence of impurities on the possible supersolid transition in 4He by systematically enriching isotopically pure samples with 3He. The addition of 3He broadens the onset of nonclassical rotational inertia and shifts it to higher temperature, suggesting that the phenomenon is correlated with the condensation of 3He atoms onto the dislocation network in solid 4He.

Nonclassical rotational inertia in helium crystals.

It has been proposed that the observed nonclassical rotational inertia (NCRI) in solid helium results from the superflow of thin liquid films along interconnected grain boundaries within the sample. We have observed NCRI in large (4)He crystals grown at constant temperature and pressure, demonstrating that the superfluid grain boundary model cannot explain the phenomenon.