Liquid-vapor oscillations of water in hydrophobic nanopores

Water plays a key role in biological membrane transport. In ion channels and water-conducting pores (aquaporins), one dimensional confinement in conjunction with strong surface effects changes the physical behavior of water. In molecular dynamics simulations of water in short (0.8 nm) hydrophobic pores the water density in the pore fluctuates on a nanosecond time scale. In long simulations (460 ns in total) at pore radii ranging from 0.35 nm to 1.0 nm we quantify the kinetics of oscillations between a liquid-filled and a vapor-filled pore. This behavior can be explained as capillary evaporation alternating with capillary condensation, driven by pressure fluctuations in the water outside the pore. The free energy difference between the two states depends linearly on the radius. The free energy landscape shows how a metastable liquid state gradually develops with increasing radius. For radii larger than ca. 0.55 nm it becomes the globally stable state and the vapor state vanishes. One dimensional confinement affects the dynamic behavior of the water molecules and increases the self diffusion by a factor of two to three compared to bulk water. Permeabilities for the narrow pores are of the same order of magnitude as for biological water pores. Water flow is not continuous but occurs in bursts. Our results suggest that simulations aimed at collective phenomena such as hydrophobic effects may require simulation times longer than 50 ns. For water in confined geometries, it is not possible to extrapolate from bulk or short time behavior to longer time scales.Comment: 20 pages, 4 figures, 3 tables; to be published in Proc. Natl. Acad. Sci. US

The effect of wave-particle interactions on low energy cutoffs in solar flare electron spectra

Solar flare hard X-ray spectra from RHESSI are normally interpreted in terms of purely collisional electron beam propagation, ignoring spatial evolution and collective effects. In this paper we present self-consistent numerical simulations of the spatial and temporal evolution of an electron beam subject to collisional transport and beam-driven Langmuir wave turbulence. These wave-particle interactions represent the background plasma's response to the electron beam propagating from the corona to chromosphere and occur on a far faster timescale than coulomb collisions. From these simulations we derive the mean electron flux spectrum, comparable to such spectra recovered from high resolution hard X-rays observations of solar flares with RHESSI. We find that a negative spectral index (i.e. a spectrum that increases with energy), or local minima when including the expected thermal spectral component at low energies, occurs in the standard thick-target model, when coulomb collisions are only considered. The inclusion of wave-particle interactions does not produce a local minimum, maintaining a positive spectral index. These simulations are a step towards a more complete treatment of electron transport in solar flares and suggest that a flat spectrum (spectral index of 0 to 1) down to thermal energies maybe a better approximation instead of a sharp cut-off in the injected electron spectrum.Comment: 6 pages, 5 figures, accepted by ApJ

Do solar decimetric spikes originate in coronal X-ray sources?

In the standard solar flare scenario, a large number of particles are accelerated in the corona. Nonthermal electrons emit both X-rays and radio waves. Thus, correlated signatures of the acceleration process are predicted at both wavelengths, coinciding either close to the footpoints of a magnetic loop or near the coronal X-ray source. We attempt to study the spatial connection between coronal X-ray emission and decimetric radio spikes to determine the site and geometry of the acceleration process. The positions of radio-spike sources and coronal X-ray sources are determined and analyzed in a well-observed limb event. Radio spikes are identified in observations from the Phoenix-2 spectrometer. Data from the Nan\c{c}ay radioheliograph are used to determine the position of the radio spikes. RHESSI images in soft and hard X-ray wavelengths are used to determine the X-ray flare geometry. Those observations are complemented by images from GOES/SXI. We find that decimetric spikes do not originate from coronal X-ray flare sources contrary to previous expectations. However, the observations suggest a causal link between the coronal X-ray source, related to the major energy release site, and simultaneous activity in the higher corona.Comment: 4 pages, 3 figures, A&AL accepte

Gene delivery to in situ veins: Differential effects of adenovirus and adeno-associated viral vectors

AbstractPurpose: Gene transfer offers the potential to modify vein graft biology at the time of surgical implantation. Efficiency of gene delivery, stability of expression, and host responses are critical parameters for candidate vectors. We compared the effects of intraluminal exposure with adenovirus (AD) and adeno-associated virus (AAV) vectors on transgene expression and monocyte adhesion (MA) in treated vein segments. Methods: Adult New Zealand white rabbits (N = 51) were anesthetized, and the jugular veins were cannulated bilaterally. Veins were gently distended with either vector (2·108 to 1·1010 infective particles/mL) or vehicle (control) for 30 minutes, after which venous flow was restored. AD and AAV vectors encoding for the marker genes β-galactosidase (LacZ) and green fluorescent protein (GFP) were used. Vessels were explanted 2 to 40 days postinfection for analysis of gene expression (X-gal staining, reverse transcriptase-polymerase chain reaction), MA, and immunohistochemistry. Ex vivo adhesion assays used 51Cr-labeled THP-1 cells. Statistical significance was tested by using analysis of variance with a P value less than.05. Results: All animals survived, and all treated veins were patent at sacrifice. Intraluminal exposure to AD at a titer of 1·109 resulted in near complete transduction of the endothelium at 2 days, with no detectable expression by day 14. At an equal titer of infectious particles, transgene expression was markedly less for AAV at 2 to 7 days, but improved at 2 weeks and persisted to 40 days. MA was significantly increased 2 days after AD exposure (2.7-fold vs control, *P <.002); AAV treatment had no discernible effect on MA. Conclusion: AD-mediated gene transfer to vein segments resulted in robust, transient gene expression that disappeared after 2 weeks. In comparison, AAV-mediated gene delivery was less efficient, but resulted in delayed onset, persistent expression beyond 30 days. AD exposure induced an early increase in MA to the vein surface that was not seen with AAV treatment. Current generations of both AD and AAV vectors have significant, albeit different, limitations for vascular gene therapy. (J Vasc Surg 2000;31:1149-59.

PAI-1 secretion of endometrial and endometriotic cells is Smad2/3- and ERK1/2-dependent and influences cell adhesion

In the endometrium transforming growth factor-betas (TGF-ßs) are involved mainly in menstruation and endometriosis. After binding of the ligands to the high-affinity receptors, TGF-ß receptors (TBR1 and TBR2), TGF-ßs activate Smad signaling to modulate gene expression and cellular functions. However, recently also Smad-independent pathways have been studied in more details. To evaluate both pathways, we have analyzed TGF-ß signaling in human endometrial and endometriotic cells. Although endometrial and endometriotic cells secrete TGF-ß1, secretion by stromal cells was higher compared to epithelial cells. In contrast, secretion of TGF-ß2 was higher in endometriotic stromal and endometriotic epithelial cells compared to normal endometrial cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-ß1 or TGF-ß2 increased Smad-dependent secretion of plasminogen activator inhibitor-1 (PAI-1) dramatically in all three cell lines. Of note, endometriotic cells secreted clearly higher levels of PAI-1 compared to endometrial cells. Whereas a TBR1 kinase inhibitor completely blocked the TGF-ß1 or TGF-ß2-induced PAI-1 secretion, an ERK1/2 inhibitor only partially reduced PAI-1 secretion. This inhibition was not dependent on epidermal growth factor receptor (EGFR) activation by phosphorylation but on kinase activity of the TBR1. Finally, treatment of endometrial and endometriotic cell lines with recombinant PAI-1 showed reduced cell adhesion, especially of the endometrial cells. In summary, our results demonstrate that both Smad-dependent and TBR1-dependent ERK1/2 pathways are necessary for TGF-ß-dependent high level secretion of PAI-1, which might increase cellular deadhesion

Subjective and Objective Assessment of Taste and Smell Sensation in Advanced Cancer

Context: Taste and smell abnormalities (TSA) occur throughout the cancer trajectory regardless of cancer primary site and contribute to cancer-associated malnutrition. TSA etiology is poorly understood. Tumor-related inflammation is a possible cause. Objective: This study examined the prevalence, characteristics, and severity of TSA in advanced cancer and explored the relationship between TSA and nutritional status. No previous study combined subjective and objective measures for both taste and smell assessment in this population. Method: Consecutive advanced cancer hospice patients were recruited. A modified version of the “Taste and Smell Survey” assessed subjective TSA. Validated taste strips and “Sniffin’ Sticks” were the objective measures. The abridged patient-generated subjective global assessment evaluated nutritional status. Results: A 93% prevalence of TSA in 30 patients with advanced cancer was identified. When subjective and objective evaluations were combined, 28 had taste abnormalities, 24 smell abnormalities, and 24 both. Taste changes included “persistent bad taste” (n ¼ 18) and changes in how basic tastes were perceived. Half reported smell was not “as strong” as prediagnosis, while more than half (n ¼ 16) had an objective smell abnormality. Most (97%) were at risk of malnutrition. Fatigue, dry mouth, early satiety, and anorexia were common nutrition-impact symptoms. No statistically significant relationship was found between TSA and malnutrition scores. Conclusions: TSA were highly prevalent. Subjective taste and smell changes did not always accord with objective TSA, suggesting both assessments are valuable. TSA characteristics varied, and particular foods tasted and smelled different and were not enjoyed as before. TSA are common, high-impact problems in advanced cancer

Clinical signs of trachoma are prevalent among Solomon Islanders who have no persistent markers of prior infection with Chlamydia trachomatis.

Background: The low population-prevalence of trachomatous trichiasis and high prevalence of trachomatous inflammation-follicular (TF) provide contradictory estimates of the magnitude of the public health threat from trachoma in the Solomon Islands. Improved characterisation of the biology of trachoma in the region may support policy makers as they decide what interventions are required. Here, age-specific profiles of anti-Pgp3 antibodies and conjunctival scarring were examined to determine whether there is evidence of ongoing transmission and pathology from ocularChlamydia trachomatis (Ct)infection.Methods:A total of 1511 individuals aged ≥1 year were enrolled from randomly selected households in 13 villages in which &gt;10% of children aged 1-9 years had TF prior to a single round of azithromycin mass drug administration undertaken six months previously. Blood was collected to be screened for antibodies to theCtantigen Pgp3. Tarsal conjunctival photographs were collected for analysis of scarring severity.Results:Anti-Pgp3 seropositivity was 18% in 1-9 year olds, sharply increasing around the age of sexual debut to reach 69% in those over 25 years. Anti-Pgp3 seropositivity did not increase significantly between the ages of 1-9 years and was not associated with TF (p=0.581) or scarring in children (p=0.472). Conjunctival scars were visible in 13.1% of photographs. Mild (p&lt;0.0001) but not severe (p=0.149) scars increased in prevalence with age.Conclusions:Neither conjunctival scars nor lymphoid follicles were associated with antibodies toCt,suggesting that they are unlikely to be a direct result of ocularCtinfection.Clinical signs of trachoma were prevalent in this population but were not indicative of the underlying rates ofCtinfection. The current World Health Organization guidelines for trachoma elimination indicated that this population should receive intervention with mass distribution of antibiotics, but the data presented here suggest that this may not have been appropriate

Pathprinting: An integrative approach to understand the functional basis of disease

New strategies to combat complex human disease require systems approaches to biology that integrate experiments from cell lines, primary tissues and model organisms. We have developed Pathprint, a functional approach that compares gene expression profiles in a set of pathways, networks and transcriptionally regulated targets. It can be applied universally to gene expression profiles across species. Integration of large-scale profiling methods and curation of the public repository overcomes platform, species and batch effects to yield a standard measure of functional distance between experiments. We show that pathprints combine mouse and human blood developmental lineage, and can be used to identify new prognostic indicators in acute myeloid leukemia. The code and resources are available at http://​compbio.​sph.​harvard.​edu/​hidelab/​pathprin

Observations of conduction driven evaporation in the early rise phase of solar flares

&lt;p&gt;&lt;b&gt;Context:&lt;/b&gt; The classical flare picture features a beam of electrons, which were accelerated in a site in the corona, hitting the chromosphere. The electrons are stopped in the dense chromospheric plasma, emitting bremsstrahlung in hard X-rays. The ambient material is heated by the deposited energy and expands into the magnetic flare loops, a process termed chromospheric evaporation. In this view hard X-ray emission from the chromosphere is succeeded by soft-X-ray emission from the hot plasma in the flare loop, the soft X-ray emission being a direct consequence of the impact of the non-thermal particle beam. However, observations of events exist in which a pronounced increase in soft X-ray emission is observed minutes before the onset of the hard X-ray emission. Such pre-flare emission clearly contradicts the classical flare picture.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Aims:&lt;/b&gt; For the first time, the pre-flare phase of such solar flares is studied in detail. The aim is to understand the early rise phase of these events. We want to explain the time evolution of the observed emission by means of alternative energy transport mechanisms such as heat conduction.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; RHESSI events displaying pronounced pre-flare emission were analyzed in imaging and spectroscopy. The time evolution of images and full sun spectra was investigated and compared to the theoretical expectations from conduction driven chromospheric evaporation. Results. The pre-flare phase is characterized by purely thermal emission from a coronal source with increasing emission measure and density. After this earliest phase, a small non-thermal tail to higher energies appears in the spectra, becoming more and more pronounced. However, images still only display one X-ray source, implying that this non-thermal emission is coronal. The increase of emission measure and density indicates that material is added to the coronal region. The most plausible origin is evaporated material from the chromosphere. Energy provided by a heat flux is capable of driving chromospheric evaporation. We show that the often used classical Spitzer treatment of the conductive flux is not applicable. The conductive flux is saturated. During the preflare-phase, the temperature of the coronal source remains constant or increases. Continuous heating in the corona is necessary to explain this observation.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The observations of the pre-flare phase of four solar flares are consistent with chromospheric evaporation driven by a saturated heat flux. Additionally, continuous heating in the corona is necessary to sustain the observed temperature.&lt;/p&gt

Towards a Proof Theory of G\"odel Modal Logics

Analytic proof calculi are introduced for box and diamond fragments of basic modal fuzzy logics that combine the Kripke semantics of modal logic K with the many-valued semantics of G\"odel logic. The calculi are used to establish completeness and complexity results for these fragments