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Papers by David Alexander

Current medicinal chemistry, 2003

Gap junctions are unique intercellular channels that connect the cytoplasm of adjacent cells. The... more Gap junctions are unique intercellular channels that connect the cytoplasm of adjacent cells. They are the only channels that mediate the direct cytoplasmic exchange of small hydrophilic molecules between cells--a process called gap junctional communication. Formed by a family of integral membrane proteins called connexins, gap junctions are dynamic multifunctional complexes that are essential for healthy vertebrate development and physiology. Defects in connexin proteins, and, therefore, in gap junctional communication, are associated with a large variety of pathologies in humans and experimental animals. Thus, knowledge of the molecules that pass through gap junction channels is extremely important. However, aside from some notable cases, the repertoire of biologically important transjunctional molecules remains relatively unexplored. Indeed, the study of the intercellular transfer of endogenous molecules presents formidable challenges. Here we review developments in identifying biologically relevant molecules that pass between cells through gap junction channels.

Journal of bacteriology, 2009

Mycobacterium avium comprises genetically related yet phenotypically distinct subspecies. Consist... more Mycobacterium avium comprises genetically related yet phenotypically distinct subspecies. Consistent with their common origin, whole-genome sequence comparisons have revealed extensive synteny among M. avium organisms. However, the sequenced strains also display numerous regions of heterogeneity that likely contribute to the diversity of the individual subspecies. Starting from a phylogenetic framework derived by multilocus sequence analysis, we examined the distribution of 25 large sequence polymorphisms across a panel of genetically defined M. avium strains. This distribution was most variable among M. avium subsp. hominissuis isolates. In contrast, M. avium subsp. paratuberculosis strains exhibited a characteristic profile, with all isolates containing a set of genomic insertions absent from other M. avium strains. The emergence of the pathogen from its putative M. avium subsp. hominissuis ancestor entailed the acquisition of approximately 125 kb of novel genetic material, followed by a second phase, characterized by reductive genomics. One genomic deletion is common to all isolates while additional deletions distinguish two major lineages of M. avium subsp. paratuberculosis. For the average strain, these losses total at least 38 kb (sheep lineage) to 90 kb (cattle lineage). This biphasic pattern of evolution, characterized by chromosomal gene acquisition with subsequent gene loss, describes the emergence of M. avium subsp. paratuberculosis and may serve as a general model for the origin of pathogenic mycobacteria.

Astrophysical Journal, 2011

We employ the DAVE (differential affine velocity estimator, Schuck 2005; 2006) tracking technique... more We employ the DAVE (differential affine velocity estimator, Schuck 2005; 2006) tracking technique on a time series of MDI/1m high spatial resolution line- of-sight magnetograms to measure the photospheric flow velocity for three newly emerging bipolar active regions. We separately calculate the magnetic helicity injection rate of the leading and following polarities to confirm or refute the magnetic helicity asymmetry, found by Tian & Alexander (2009) using MDI/96m low spatial resolution magnetograms. Our results demonstrate that the magnetic helicity asymmetry is robust being present in the three active regions studied, two of which have an observed balance of the magnetic flux. The magnetic helicity injection rate measured is found to depend little on the window size selected, but does depend on the time interval used between the two successive magnetograms tracked. It is found that the measurement of the magnetic helicity injection rate performs well for a window size between 12x10 and 18x15 pixels, and at a time interval {\Delta}t=10 minutes. Moreover, the short-lived magnetic structures, 10-60 minutes, are found to contribute 30-50% of the magnetic helicity injection rate. Comparing with the results calculated by MDI/96m data, we find that the MDI/96m data, in general, can outline the main trend of the magnetic properties, but they significantly underestimate the magnetic flux in strong field region and are not appropriate for quantitative tracking studies, so provide a poor estimate of the amount of magnetic helicity injected into the corona.

Cancer research, Jan 15, 2004

The growth of many types of cancer cells can be controlled by surrounding normal cells. However, ... more The growth of many types of cancer cells can be controlled by surrounding normal cells. However, mechanisms underlying this phenomenon have not been defined. We used a layered culture system to investigate how nontransformed cells suppress the growth of neighboring transformed cells. Direct physical contact between transformed and nontransformed cells was required for growth suppression of transformed cells in this system; communication by diffusible factors was not sufficient. However, significant gap junctional communication was not required, indicating that other intercellular junctions mediated this growth regulatory response. We also report that the Src kinase activity in transformed cells was not directly inhibited by contact with nontransformed cells. Instead, nontransformed cells increased the expression of serum deprivationresponse protein and the transcription factor four and a half LIM domain 1 in tumor cells. In addition, these results suggest mechanisms by which normal cells may block Wnt signaling, inhibit insulin-like growth factor activity, and promote host recognition of neighboring tumor cells.

PLoS pathogens, 2005

Apicomplexan parasites, including Toxoplasma gondii and Plasmodium sp., are obligate intracellula... more Apicomplexan parasites, including Toxoplasma gondii and Plasmodium sp., are obligate intracellular protozoa. They enter into a host cell by attaching to and then creating an invagination in the host cell plasma membrane. Contact between parasite and host plasma membranes occurs in the form of a ring-shaped moving junction that begins at the anterior end of the parasite and then migrates posteriorly. The resulting invagination of host plasma membrane creates a parasitophorous vacuole that completely envelops the now intracellular parasite. At the start of this process, apical membrane antigen 1 (AMA1) is released onto the parasite surface from specialized secretory organelles called micronemes. The T. gondii version of this protein, TgAMA1, has been shown to be essential for invasion but its exact role has not previously been determined. We identify here a trio of proteins that associate with TgAMA1, at least one of which associates with TgAMA1 at the moving junction. Surprisingly, these new proteins derive not from micronemes, but from the anterior secretory organelles known as rhoptries and specifically, for at least two, from the neck portion of these club-shaped structures. Homologues for these AMA1-associated proteins are found throughout the Apicomplexa strongly suggesting that this moving junction apparatus is a conserved feature of this important class of parasites. Differences between the contributing proteins in different species may, in part, be the result of selective pressure from the different niches occupied by these parasites. Citation: Alexander DL, Mital J, Ward GE, Bradley P, Boothroyd JC (2005) Identification of the moving junction complex of Toxoplasma gondii: A collaboration between distinct secretory organelles. PLoS Pathog 1(2): e17.

Eukaryotic cell, 2006

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) coimmunoprecipitates with the Plasmodium... more Plasmodium falciparum apical membrane antigen 1 (PfAMA1) coimmunoprecipitates with the Plasmodium homologue of TgRON4, a secreted rhoptry neck protein of Toxoplasma gondii that migrates at the moving junction in association with TgAMA1 during invasion. PfRON4 also originates in the rhoptry necks, suggesting that this unusual collaboration of micronemes and rhoptries is a conserved feature of Apicomplexa.

Inhalation toxicology, 2008

There are many ways in which the dose can be expressed in inhalation toxicology studies. This can... more There are many ways in which the dose can be expressed in inhalation toxicology studies. This can lead to confusion when comparing results from studies performed in different laboratories. A working party of the Association of Inhalation Toxicologists has reviewed this subject in detail and has collected data from 10 inhalation laboratories and used these data to determine a new algorithm for the calculation of Respiratory Minute Volume (RMV), one of the most important factors in the calculation of delivered dose. The recommendations of the working party for regulatory inhalation toxicology studies with pharmaceuticals are as follows: 1. The dose should be reported as the delivered dose calculated according to the formula: DD = C x RMV x D(xIF)/BW, where DD = delivered dose (mg/Kg); C = concentration of substance in air (mg/L); RMV =respiratory minute volume or the volume of air inhaled in one minute (L/min); D = duration of exposure (min); IF = proportion by weight of particles that are inhalable by the test species, the inhalable fraction (inclusion of this parameter is not essential provided that the aerosol has reasonable respirability for the intended species. If it is included, the way in which it is determined should be clearly stated); BW = bodyweight (Kg). 2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to the formula:RMV(L/min) = 0.608 x BW(Kg)(0.852). 3. If deposited dose or the amount of material actually retained inthe respiratory tract is presented as supplementary information,the way in which it is calculated should be clearly stated.4. Dose should always be presented in mg/Kg but may also bepresented in other ways, such as mg/unit body surface area, as supplementary information.

Journal of cell science, Jan 15, 2002

p67 is a lysosomal type I membrane glycoprotein of Trypanosoma brucei. In procyclic stage cells p... more p67 is a lysosomal type I membrane glycoprotein of Trypanosoma brucei. In procyclic stage cells p67 trafficks to the lysosome without modification, but in the bloodstream stage Golgi processing adds poly-N-acetyllactosamine to N-glycans. In both stages proteolytic fragmentation occurs in the lysosome, but turnover is approximately nine times faster in bloodstream cells. Trafficking of wildtype p67 and mutants missing the cytoplasmic (p67DeltaCD) or cytoplasmic/transmembrane domains (p67DeltaTM) was monitored by pulse-chase, surface biotinylation and immunofluorescence. Overexpressed wildtype p67 trafficks normally in procyclics, but some leaks to the cell surface suggesting that the targeting machinery is saturable. p67DeltaCD and p67DeltaTM are delivered to the cell surface and secreted, respectively. The membrane/cytoplasmic domains function correctly in procyclic cells when fused to GFP indicating that these domains are sufficient for stage-specific lysosomal targeting. In contrast, p67 wildtype and deletion reporters are overwhelmingly targeted to the lysosome and degraded in bloodstream cells. These findings suggest that either redundant developmentally regulated targeting signals/machinery are operative in this stage or that the increased endocytic activity of bloodstream cells prevents export of the deletion reporters.

Inertial confinement fusion research at Los Alamos National Laboratory is focused on high-leverag... more Inertial confinement fusion research at Los Alamos National Laboratory is focused on high-leverage areas of thermonuclear ignition to which LANL can apply its historic strengths and that are complementary to high-energy-density-physics topics. Using the Trident and Omega laser facilities, experiments are pursued in laser-plasma instabilities, symmetry, Be technologies, neutron and fusion-product diagnostics, and defect hydrodynamics.

Astrophysical Journal, 2008

ABSTRACT We present observations from 2007 March 2 of a partial filament eruption characterized b... more ABSTRACT We present observations from 2007 March 2 of a partial filament eruption characterized by two distinct phases of writhing motions: a quasi-static, slowly evolving phase followed by a rapid kinking phase showing a bifurcation of the filament. The quasi-static kinking motions ...

The Astrophysical Journal, 2006

The Astrophysical Journal, 2000

In a recent Letter, Reale & Peres demonstrated that this method can explain the almost isothe... more In a recent Letter, Reale & Peres demonstrated that this method can explain the almost isothermal appearance of T RACE loops (observed by Lenz et al.) as derived from the lter-ratio method. From model-tting of the 171 and 195 uxes of 41 loops, which have loop half-...

Publications of The Astronomical Society of The Pacific, 2007

We describe how the James Webb Space Telescope (JWST) Near-Infrared Spectrograph's (NIRSpec's) de... more We describe how the James Webb Space Telescope (JWST) Near-Infrared Spectrograph's (NIRSpec's) detectors will be read out, and present a model of how noise scales with the number of multiple non-destructive reads sampling-up-the-ramp. We believe that this noise model, which is validated using real and simulated test data, is applicable to most astronomical near-infrared instruments. We describe some non-ideal behaviors that have been observed in engineering grade NIRSpec detectors, and demonstrate that they are unlikely to affect NIRSpec sensitivity, operations, or calibration. These include a HAWAII-2RG reset anomaly and random telegraph noise (RTN). Using real test data, we show that the reset anomaly is: (1) very nearly noiseless and (2) can be easily calibrated out. Likewise, we show that large-amplitude RTN affects only a small and fixed population of pixels. It can therefore be tracked using standard pixel operability maps.

We use deep far-IR, submm, radio and X-ray imaging and mid-IR spectroscopy to explore the nature ... more We use deep far-IR, submm, radio and X-ray imaging and mid-IR spectroscopy to explore the nature of a sample of Spitzer-selected dust-obscured galaxies (DOGs) in GOODS-N. A sample of 79 galaxies satisfy the criteria R − [24] > 14 (Vega) down to S 24 > 100 µJy (median flux density S 24 = 180 µJy). Twelve of these galaxies have IRS spectra available which we use to measure redshifts and classify these objects as being dominated by star formation or active galactic nuclei (AGN) activity in the mid-IR. The IRS spectra and Spitzer photometric redshifts confirm that the DOGs lie in a tight redshift distribution around z ∼ 2. Based on mid-IR colors, 80% of DOGs are likely dominated by star formation; the stacked X-ray emission from this sub-sample of DOGs is also consistent with star formation. Since only a small number of DOGs are individually detected at far-IR and submm wavelengths, we use a stacking analysis to determine the average flux from these objects and plot a composite IR (8-1000 µm) spectral energy distribution (SED). The average luminosity of these star forming DOGs is L IR ∼ 1 × 10 12 L ⊙ . We compare the average star forming DOG to the average bright (S 850 > 5 mJy) submillimeter galaxy (SMG); the S 24 > 100 µJy DOGs are 3 times more numerous but 8 times less luminous in the IR. The far-IR SED shape of DOGs is similar to that of SMGs (average dust temperature of around 30 K) but DOGs have a higher mid-IR to far-IR flux ratio. The average star formation-dominated DOG has a star formation rate of 200 M ⊙ yr −1 which, given their space density, amounts to a contribution of 0.01 M ⊙ yr −1 Mpc −3 (or 5-10%) to the star formation rate density at z ∼ 2. We use the composite SED to predict the average flux of DOGs in future Herschel/PACS 100 µm and SCUBA-2 450 µm surveys and show that the majority of them will be detected.

The Astrophysical …, 2000

The three-dimensional structure of solar active region NOAA 7986 observed on 1996 August 30 with ... more The three-dimensional structure of solar active region NOAA 7986 observed on 1996 August 30 with the Extreme-Ultraviolet Imaging Telescope (EIT) on board the Solar and Heliospheric Observatory (SOHO) is analyzed. We develop a new method of dynamic stereoscopy to reconstruct the threedimensional geometry of dynamically changing loops, which allows us to determine the orientation of 1 Current address : Lockheed-Martin ATC, Solar and Astrophysics Laboratory, Department H1-12, Building 252, 3251 Hanover Street, Palo Alto, CA 94304 ; aschwanden=sag.lmsal.com. temperature of the solar corona ranges around T e B 1.5 MK, this temperature seems to reÑect the most likely steady state condition of coronal structures, demarcating at the same time a watershed where cooling and heating processes start to lose equilibrium. It is therefore a physically meaningful choice to distinguish between cool2 and hot loops 2 The temperature range of MK that we denote as cool here is T e [ 1.5 sometimes also termed intermediate temperatures (e.g., Brown 1996), whereas loops with temperatures of K are referred to as cool T e [ 105 loops (e.g., Martens & Kuin 1982).

The Astrophysical …, 1999

ABSTRACT We report here, for the rst time, on spatial oscillations of coronal loops, which were ... more ABSTRACT We report here, for the rst time, on spatial oscillations of coronal loops, which were detected in extreme-ultraviolet wavelengths (171 with the Transition Region and Coronal Explorer, in the tem-Aé) perature range of MK. The observed loop oscillations occurred ...

The deep X-ray, optical, and far-infrared fields that constitute GOODS are sensitive to obscured ... more The deep X-ray, optical, and far-infrared fields that constitute GOODS are sensitive to obscured AGN (N H 10 22 cm −2 ) at the quasar epoch (z ∼ 2 − 3), as well as to unobscured AGN as distant as z∼7. Luminous X-ray emission is a sign of accretion onto a supermassive black hole and thus reveals all but the most heavily obscured AGN. We combine X-ray luminosity functions with appropriate spectral energy distributions for AGN to model the X-ray, optical and far-infrared flux distributions of the X-ray sources in the GOODS fields. A simple model based on the unified paradigm for AGN, with ∼ 3 times as many obscured AGN as unobscured, successfully reproduces the z-band flux distributions measured in -2the deep HST ACS observations on the GOODS North and South fields. This model is also consistent with the observed spectroscopic and photometric redshift distributions once selection effects are considered. The previously reported discrepancy between observed spectroscopic redshift distributions and the predictions of population synthesis models for the X-ray background can be explained by bias against the most heavily obscured AGN generated both by X-ray observations and the identification of sources via optical spectroscopy. We predict the AGN number counts for Spitzer MIPS 24 µm and IRAC 3.6-8 µm observations in the GOODS fields, which will verify whether most AGN in the early Universe are obscured in the optical. Such AGN should be very bright far-infrared sources and include some obscured AGN missed even by X-ray observations.