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Introduction
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July 2007 - present
April 1999 - May 1999
April 1997 - June 2007
Publications
Publications (199)
We present new, deep, narrow- and broadband Hubble Space Telescope observations of seven of the most star-forming brightest cluster galaxies (BCGs). Continuum-subtracted [O II ] maps reveal the detailed, complex structure of warm ( T ∼ 10 ⁴ K) ionized gas filaments in these BCGs, allowing us to measure spatially resolved star formation rates (SFRs)...
We present new, deep, narrow- and broad-band Hubble Space Telescope observations of seven of the most star-forming brightest cluster galaxies (BCGs). Continuum-subtracted [O II] maps reveal the detailed, complex structure of warm ($T \sim 10^4$ K) ionized gas filaments in these BCGs, allowing us to measure spatially-resolved star formation rates (S...
Context:
Rapid on-site evaluation (ROSE) optimizes the performance of cytology, but requires skilled handling, and smearing can make the material unavailable for some ancillary tests. There is a need to facilitate ROSE without sacrificing part of the sample.
Objective:
We evaluated the image quality of inexpensive deconvolution fluorescence micr...
For quality, interpretation, reproducibility and sharing value, microscopy images should be accompanied by detailed descriptions of the conditions that were used to produce them. Micro-Meta App is an intuitive, highly interoperable, open-source software tool that was developed in the context of the 4D Nucleome (4DN) consortium and is designed to fa...
For the information content of microscopy images to be appropriately interpreted, reproduced, and meet FAIR (Findable Accessible Interoperable and Reusable) principles, they should be accompanied by detailed descriptions of microscope hardware, image acquisition settings, image pixel and dimensional structure, and instrument performance. Nonetheles...
For the information content of microscopy images to be appropriately interpreted, reproduced, and meet FAIR (Findable Accessible Interoperable and Reusable) principles, they should be accompanied by detailed descriptions of microscope hardware, image acquisition settings, image pixel, and dimensional structure, and instrument performance. Nonethele...
A persistent basal tone in the internal anal sphincter (IAS) is essential for keeping the anal canal closed and fecal continence; its inhibition via the rectoanal inhibitory reflex (RAIR) is required for successful defecation. However, cellular signals underlying the IAS basal tone remain enigmatic. Here we report the origin and molecular mechanism...
Small-molecule fluorescent wheat germ agglutinin (WGA) conjugates are routinely used to demarcate mammalian plasma membranes, because they bind to the cell's glycocalyx. Here, we describe the derivatization of WGA with a pH-sensitive rhodamine fluorophore (pHRho; pKa = 7) to detect proton channel fluxes and extracellular proton accumulation and dep...
Small molecule fluorescent wheat germ agglutinin (WGA) conjugates are routinely used to demarcate mammalian plasma membranes because they bind to the cell's glycocalyx. Here we describe the derivatization of WGA with a pH sensitive rhodamine fluorophore (pHRho: pKa = 7) to detect proton channel fluxes and extracellular proton accumulation and deple...
We present new Atacama Large Millimeter Array observations of the molecular gas and far-infrared continuum around the brightest cluster galaxy (BCG) in the cool-core cluster MACS 1931.8-2635. Our observations reveal (1.9 ± 0.3) × 10^(10) M⊙ of molecular gas, on par with the largest known reservoirs of cold gas in a cluster core. We detect CO(1−0),...
Ion channels in myometrial cells play critical roles in spontaneous and agonist-induced uterine contraction during the menstrual cycle, pregnancy maintenance and parturition; thus identifying the genes of ion channels in these cells and determining their roles are essential to understanding the biology of reproduction. Previous studies with in vitr...
We present new ALMA observations of the molecular gas and far-infrared continuum around the brightest cluster galaxy (BCG) in the cool-core cluster MACS 1931.8-2635. Our observations reveal $1.9 \pm 0.3 \times 10^{10}$ M$_{\odot}$ of molecular gas, on par with the largest known reservoirs of cold gas in a cluster core. We detect CO(1-0), CO(3-2), a...
We investigate the evolution of star formation rates (SFRs), stellar masses, and M/L_3.4 micron ratios of brightest cluster galaxies (BCGs) in the COSMOS survey since z ~ 1 to determine the contribution of star formation to the growth-rate of BCG stellar mass over time. Through the spectral energy distribution (SED) fitting of the GALEX, CFHT, Suba...
Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is crit...
Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here...
We study the nature of the feedback mechanism required to offset cooling in the 11 CLASH brightest cluster galaxies (BCGs) that exhibit extended ultraviolet and nebular line emission features. We estimate star formation rates (SFRs), dust masses, and starburst durations using a Bayesian SED fitting technique that accounts for both stellar and dust...
Cells use plasma membrane proton fluxes to maintain cytoplasmic and extracellular pH and to mediate the co-transport of metabolites and ions. Because proton-coupled transport often involves movement of multiple substrates, traditional electrical measurements provide limited information about proton transport at the cell surface. Here we visualize v...
siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of as...
Smooth muscle sphincters exhibit basal tone and control passage of contents through organs such as the gastrointestinal tract; loss of this tone leads to disorders such as faecal incontinence. However, the molecular mechanisms underlying this tone remain unknown. Here, we show that deletion of myosin light-chain kinases (MLCK) in the smooth muscle...
Supplementary Figures 1-17, Supplementary Tables 1-2 and Supplementary References
The assembly and maintenance of most cilia and flagella rely on intraflagellar transport (IFT). Recentin vitrostudies have suggested that the calponin-homology domain in the IFT81 N-terminus and the highly basic N-terminus of IFT74 together form a module for IFT of tubulin. UsingChlamydomonasmutants for IFT81 and IFT74, we have tested this hypothes...
Smooth muscle, the major cell type of urethra, generates sufficient intraurethral pressure to prevent voiding of urine from the bladder; its dysfunction contributes to stress urinary incontinence, a pathological disorder affecting up to 30% of women and causing physical discomfort and emotional distress. However, the cellular and molecular mechanis...
Significance
The dopamine (DA) transporter (DAT) stringently controls brain DA levels. Several addictive psychostimulants, antidepressants, and attention-deficit/hyperactivity disorder (ADHD) therapeutics inhibit DAT function, and multiple DAT mutants have been reported in ADHD, autism spectrum disorder, and infantile Parkinsonism. Given that aberr...
The CLASH X-ray selected sample of 20 galaxy clusters contains ten brightest
cluster galaxies (BCGs) that exhibit significant ($>$5 $\sigma$)
extinction-corrected star formation rates (SFRs). Star formation activity is
inferred from photometric estimates of UV and H$\alpha$+[NII] emission in knots
and filaments detected in CLASH HST observations. T...
Brightest cluster galaxies (BCGs) are usually quiescent, but many exhibit
star formation. Here we exploit the opportunity provided by rest-frame UV
imaging of galaxy clusters in the CLASH (Cluster Lensing and Supernovae with
Hubble) Multi-Cycle Treasury Project to reveal the diversity of UV morphologies
in BCGs and to compare them with recent simul...
Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps1...
Background
We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in receptor-mediated endocytosis. The clinical presentation includes intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, m...
The protein nephrocystin-4 (NPHP4) is widespread in ciliated organisms, and defects in NPHP4 cause nephronophthisis and blindness in humans. To learn more about NPHP4's function, we have studied it in Chlamydomonas reinhardtii. NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CE...
Key points
Although the importance of asynchronous exocytosis is becoming clearer, not enough is known about its roles and mechanisms.
Here we describe the nature of exocytosis in mouse adrenal chromaffin cells during low frequency physiological stimulation, i.e. 0.5 Hz, providing new views.
We report that less than 10% of all catecholaminergic exo...
Focus stabilization is critical for many imaging modalities like TIRF, PALM and STORM. The focus stabilization device presented here, named pgFocus, is an open source and open hardware solution that can be integrated into microscopes with an existing objective positioner. pgFocus is a programmable and inexpensive circuit board consisting of a micro...
Dopaminergic signaling profoundly impacts rewarding behaviors, movement, and executive function. The presynaptic dopamine (DA) transporter (DAT) recaptures released DA, thereby limiting synaptic DA availability and maintaining dopaminergic tone. DAT constitutively internalizes and PKC activation rapidly accelerates DAT endocytosis, resulting in DAT...
Bronchodilators are a standard medicine for treating airway obstructive diseases, and β2 adrenergic receptor agonists have been the most commonly used bronchodilators since their discovery. Strikingly, activation of G-protein-coupled bitter taste receptors (TAS2Rs) in airway smooth muscle (ASM) causes a stronger bronchodilation in vitro and in vivo...
Bronchodilators are a standard medicine for treating airway obstructive diseases, and b2 adrenergic receptor agonists have been the most commonly used bronchodilators since their discovery. Strikingly, activation of G-protein-coupled bitter taste receptors (TAS2Rs) in airway smooth muscle (ASM) causes a stronger bronchodilation in vitro and in vivo...
Characteristics of [Ca2+]i and contractile responses to bitter tastants and diltiazem in human ASM. (A) Bitter tastants reversed the [Ca2+]i rise and cell shortening induced by Mch. Measurements were taken at the steady state levels in response to Mch and chloroquine. The cell length before stimulation was considered as 100%. *p<0.05 paired Student...
KCl activates L-type VDCCs to increase [Ca2+]i and cause contraction in mouse ASM. (A) KCl failed to generate any global [Ca2+]i increase in the absence of extracellular Ca2+ in isolated single ASM cells. (i) A representative [Ca2+]i response to 60 mM KCl in the presence of extracellular Ca2+. (ii, iii, iv) three examples showing that the same conc...
This clip shows 1 mM chloro reversed the 100 µM Mch-induced increase in [Ca2+]i and cell shortening; the first 120 images of this clip were analyzed and plotted in Figure 2A. The images are displayed as fluorescence intensity (rather than ΔF/F0) because the cell changes its shape dramatically in response to stimuli (and changing thickness makes ΔF/...
Bitter tastant chloroquine dose-dependently increased [Ca2+]i in resting single cells (A) without a significant effect on the contractility (B) of relaxed mouse airways. Results are mean ± SEM, (n = 5–30 cells in (A) and 7 airway rings in (B)). Dose response curves in (A) were generated on the basis of the responses to single dose administration, w...
KCl activates VDCCs in cholinergic nerves and ASM. (A) Atropine dose-dependently inhibited Mch-induced mouse airway contraction. The left panels display representative contractile responses to 3 µM Mch in the absence or the presence of atropine as marked near the traces, and the right panel shows the mean values (mean ± SEM; n = 4–8) of inhibition...
Ca2+ influx plays a major role in producing and maintaining Mch-induced increases in [Ca2+]i and contraction in mouse ASM. (A) In Ca2+ free medium, the tension generated by Mch was less than 20% of that in the presence of extracellular Ca2+. ***p<0.001, Student's paired t-test, n = 9 airway rings for the group with Ca2+, and n = 10 airway rings for...
Role of L-type Ca2+ channel activation in Mch-induced contraction in mouse airway. (A) Left panel: L-type VDCC blocker diltiazem dose-dependently reversed Mch-induced contraction (using tension as a proxy measure). Right panel: results for n = 6 airway rings. % relaxation was calculated the same as in Figure S2B. (B) Diltiazem inhibited Mch- and KC...
Primers for Reverse Transcription-PCR.
(TIFF)
[This corrects the article on p. e1001501 in vol. 11.].
In addition to its role as a morphogen, Sonic hedgehog (Shh) has also been shown to function as a guidance factor that directly acts on the growth cones of various types of axons. However, the noncanonical signaling pathways that mediate the guidance effects of Shh protein remain poorly understood. We demonstrate that a novel signaling pathway cons...
Cell surface receptors and other proteins internalize through diverse mechanisms at the plasma membrane and are sorted to different destinations. Different subpopulations of early endosomes have been described, raising the question of whether different internalization mechanisms deliver cargo into different subsets of early endosomes. To address th...
The neuropilins (NRPs) contribute to the function of cancer cells in their capacity as VEGF receptors. Given that NRP2 is induced in breast cancer and correlates with aggressive disease, we examined the role of NRP2 in regulating the interaction of breast cancer cells with the ECM. Using epithelial cells from breast tumors, we defined NRP2(high) an...
The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus. We have shown that L-type Ca(2+) channels in terminals of hypothalamic magnocellular neurons are coupled to RyRs, as they are in skeletal muscle, allowing voltage-induced Ca(2+) release (VICaR) from internal Ca(2...
Short-lived, localized Ca(2+) events mediate Ca(2+) signaling with high efficiency and great fidelity largely as a result of the close proximity between Ca(2+)-permeable ion channels and their molecular targets. However, in most cases, direct evidence of the spatial relationship between these two types of molecules is lacking, and, thus, mechanisti...
Context.—Advances in microscopy enable visualization of a broad range of new morphologic features.
Objective.—To review and illustrate advances in microscopy with relevance to pathologists.
Data Sources.—Literature review and new observations.
Results.—Fluorescence microscopy enables multiantigen detection; allows novel optical-sectioning technique...
Advances in microscopy enable visualization of a broad range of new morphologic features.
To review and illustrate advances in microscopy with relevance to pathologists.
Literature review and new observations.
Fluorescence microscopy enables multiantigen detection; allows novel optical-sectioning techniques, with some advantages compared to paraffi...
Protein kinase B/Akt protein kinases control an array of diverse functions, including cell growth, survival, proliferation, and metabolism. We report here the identification of pleckstrin homology-like domain family B member 1 (PHLDB1) as an insulin-responsive protein that enhances Akt activation. PHLDB1 contains a pleckstrin homology domain, which...
Within the circulatory system, blood flow regulates vascular remodelling, stimulates blood stem cell formation, and has a role in the pathology of vascular disease. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act before circulation. Subsequently, endothelial cells must incorporate the...
Association of pericentrin with insulin granules was observed by immunofluorescence of purified granules and iodixinol density gradients. A. Subcellular fractionation of MIN6 cells. The fraction predicted to contain insulin secretory granules was immunostained for insulin and pericentrin, with overlay in yellow (3rd panel). Enlargement of inset (4t...
Pericentrin depletion caused insulin hypersecretion without affecting glucose-stimulated insulin biosynthesis. A. Blot of insulin immunoprecipitation from insulinoma cells incubated with low (2.5 mM) or high (25 mM) glucose for 1 h in the presence of [S35]-methionine. B. Blot of media from insulinoma cells grown in 25 mM glucose. [S35]-labeled proi...
Glucose stimulation of isolated mouse islets in vitro. A. Islets were stably transduced with pericentrin or control (scrambled) shRNAs. Immunofluorescence staining before glucose stimulations in a low glucose media (2.5 mM) showed the expected depletion of pericentrin (green) and reduction of insulin (red). Scale bar represents 10 µm. B. 1 hr stimu...
Spinning-disk confocal z-series through a mouse islet stably expressing pericentrin shRNA showed GFP expression throughout the mouse islet. The video shows GFP reporter expressed by 54% of the islet cells. DNA (blue) was visualized with DAPI. The z-series show the whole islet at 0.25 µm steps (xy pixels = 0.183 µm).
(1.06 MB MOV)
The centrosome is important for microtubule organization and cell cycle progression in animal cells. Recently, mutations in the centrosomal protein, pericentrin, have been linked to human microcephalic osteodysplastic primordial dwarfism (MOPD II), a rare genetic disease characterized by severe growth retardation and early onset of type 2 diabetes...
Within the circulatory system, blood flow regulates vascular remodelling(1), stimulates blood stem cell formation(2), and has a role in the pathology of vascular disease(3). During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act before circulation(4). Subsequently, endothelial cells must inco...