Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules

Needleman, Daniel J.,Ojeda-Lopez, Miguel A.,Raviv, Uri,Miller, Herbert P.,Li, Youli,Song, Chaeyeon,Feinstein, Stuart C.,Wilson, Leslie,Choi, Myung Chul,Safinya, Cyrus R. The Royal Society of Chemistry 2013 Faraday discussions Vol.166 No.-

<P>Microtubules (MTs) are nanometer scale hollow cylindrical biological polyelectrolytes. They are assembled from α/β-tubulin dimers, which stack to form protofilaments (PFs) with lateral interactions between PFs resulting in the curved MT. In cells, MTs and their assemblies are critical components in a range of functions from providing tracks for the transport of cargo to forming the spindle structure during mitosis. Previous studies have shown that while cations with valence equal to or larger than 3+ tend to assemble tight 3D bundles of taxol-stabilized MTs, certain divalent cations induce relatively loose 2D bundles of different symmetry (D. J. Needleman <I>et al.</I>, <I>Proc. Natl. Acad. Sci. U. S. A.</I>, 2004, <B>101</B>, 16099). Similarly, divalent cations form 2D bundles of DNA adsorbed on cationic membranes (I. Koltover <I>et al.</I>, <I>Proc. Natl. Acad. Sci. U. S. A.</I>, 2000, <B>97</B>, 14046). The bundling behavior for these biological polyelectrolyte systems is qualitatively in agreement with current theory. Here, we present results which show that, unlike the case for DNA adsorbed on cationic membranes, bundling of taxol-stabilized MTs occurs only for certain divalent cations above a critical ion concentration (<I>e.g.</I> Ca<SUP>2+</SUP>, Sr<SUP>2+</SUP>, Ba<SUP>2+</SUP>). Instead, many divalent cations pre-empt the bundling transition and depolymerize taxol-stabilized MTs at a lower counterion concentration. Although previous cryogenic TEM has shown that, in the absence of taxol, Ca<SUP>2+</SUP> depolymerizes MTs assembling in buffers containing GTP (guanosine triphosphate), our finding is surprising given the known stabilizing effects of taxol on GDP (guanosine diphosphate)-MTs. The ion concentration required for MT depolymerization decreases with increasing atomic number for the divalents Mg<SUP>2+</SUP>, Mn<SUP>2+</SUP>, Co<SUP>2+</SUP>, and Zn<SUP>2+</SUP>. GdCl<SUB>3</SUB> (3+) is found to be extremely efficient at MT depolymerization requiring ion concentrations of about 1 mM, while oligolysine (2+), is observed not to depolymerize MTs at concentrations as high as 144 mM. The surprising MT depolymerization results are discussed in the context of divalents either disrupting lateral interactions between PFs (which are strengthened for taxol containing β-tubulin), or interfering with taxol's ability to induce flexibility at the interface between two tubulin dimers in the same PF (which has been recently suggested as a mechanism by which taxol stabilizes MTs post-hydrolysis with the induced flexibility counteracting the kink between GDP-tubulin dimers in a PF).</P>

Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity

Jörg U. Schmohl,Martin Felices,Felix Oh,Alexander J. Lenvik,Aaron M. Lebeau,Jayanth Panyam,Jeffrey S. Miller,Daniel A. Vallera 대한암학회 2017 Cancer Research and Treatment Vol.49 No.4

Purpose The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 bispecific natural killer (NK) cell engager (BiKE), consisting of scFvs binding FcRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified interleukin (IL)-15 crosslinker capable of stimulating NK effector cells was introduced. Materials and Methods DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE). The construct was tested for its specificity using flow cytometry, cytotoxic determinations using chromium release assays, and lytic degranulation. IL-15–mediated expansion was measured using flow-based proliferation assays. The level of interferon (IFN)- release was measured because of its importance in the anti-cancer response. Results 1615133 TriKE induced NK cell–mediated cytotoxicity and NK expansion far greater than that achieved with BiKE devoid of IL-15. The drug binding and induction of cytotoxic degranulation was CD133+ specific and the anti-cancer activity was improved by integrating the IL-15 cross linker. The NK cell–related cytokine release measured by IFN- detection was higher than that of BiKE. NK cytokine release studies showed that although the IFN- levels were elevated, they did not approach the levels achieved with IL-12/IL-18, indicating that release was not at the supraphysiologic level. Conclusion 1615133 TriKE enhances the NK cell anti-cancer activity and provides a self-sustaining mechanism via IL-15 signaling. By improving the NK cell performance, the new TriKE represents a highly active drug against drug refractory relapse mediated by CSCs.

Glyoxal yield from isoprene oxidation and relation to formaldehyde: chemical mechanism, constraints from SENEX aircraft observations, and interpretation of OMI satellite data

Chan Miller, Christopher,Jacob, Daniel J.,Marais, Eloise A.,Yu, Karen,Travis, Katherine R.,Kim, Patrick S.,Fisher, Jenny A.,Zhu, Lei,Wolfe, Glenn M.,Hanisco, Thomas F.,Keutsch, Frank N.,Kaiser, Jennif Copernicus GmbH 2017 Atmospheric Chemistry and Physics Vol.17 No.14

<P>Abstract. Glyoxal (CHOCHO) is produced in the atmosphere by the oxidation of volatile organic compounds (VOCs). Like formaldehyde (HCHO), another VOC oxidation product, it is measurable from space by solar backscatter. Isoprene emitted by vegetation is the dominant source of CHOCHO and HCHO in most of the world. We use aircraft observations of CHOCHO and HCHO from the SENEX campaign over the southeast US in summer 2013 to better understand the CHOCHO time-dependent yield from isoprene oxidation, its dependence on nitrogen oxides (NOx ≡ NO + NO2), the behavior of the CHOCHO-HCHO relationship, the quality of OMI CHOCHO satellite observations, and the implications for using CHOCHO observations from space as constraints on isoprene emissions. We simulate the SENEX and OMI observations with the Goddard Earth Observing System chemical transport model (GEOS-Chem) featuring a new chemical mechanism for CHOCHO formation from isoprene. The mechanism includes prompt CHOCHO formation under low-NOx conditions following the isomerization of the isoprene peroxy radical (ISOPO2). The SENEX observations provide support for this prompt CHOCHO formation pathway, and are generally consistent with the GEOS-Chem mechanism. Boundary layer CHOCHO and HCHO are strongly correlated in the observations and the model, with some departure under low-NOx conditions due to prompt CHOCHO formation. SENEX vertical profiles indicate a free-tropospheric CHOCHO background that is absent from the model. The OMI CHOCHO data provide some support for this free-tropospheric background and show southeast US enhancements consistent with the isoprene source but a factor of 2 too low. Part of this OMI bias is due to excessive surface reflectivities assumed in the retrieval. The OMI CHOCHO and HCHO seasonal data over the southeast US are tightly correlated and provide redundant proxies of isoprene emissions. Higher temporal resolution in future geostationary satellite observations may enable detection of the prompt CHOCHO production under low-NOx conditions apparent in the SENEX data. </P>

The impact of incontinence etiology on artificial urinary sphincter outcomes

Adam R. Miller,Brian J. Linder,Laureano J. Rangel,David Y. Yang,Daniel S. Elliott 대한비뇨의학회 2017 Investigative and Clinical Urology Vol.58 No.4

Purpose: To evaluate the impact of incontinence etiology on artificial urinary sphincter (AUS) device outcomes. Materials and Methods: We identified 925 patients who underwent primary AUS placement from 1983 to 2011. The etiology of incontinence was categorized as radical prostatectomy alone, radical prostatectomy with radiation, benign prostate resection, and those with cryotherapy as a salvage prostate cancer treatment. Hazard regression and competing risk analyses were used to determine the association of the etiology of incontinence with device outcomes. Results: The distribution of the 4 etiologies of incontinence included: 598 patients (64.6%) treated with prostatectomy alone, 206 (22.2%) with prostatectomy and pelvic radiation therapy, 104 (11.2%) with benign prostate resection, and 17 (1.8%) with prior cryotherapy. With a median follow-up of 4.9 years (interquartile range, 1.2–8.8 years), there was significant difference in the cumulative incidence of device infection/urethral erosion events between the four etiologies (p=0.003). On multivariable analysis, prior cryotherapy (reference prostatectomy alone; hazard ratio [HR], 3.44; p=0.01), older age (HR, 1.07; p=0.0009) and history of a transient ischemic attack (HR, 2.57; p=0.04) were associated with an increased risk of device infection or erosion. Notably, pelvic radiation therapy with prostatectomy was not associated with an increased risk of device infection or erosion (reference prostatectomy alone, p=0.30). Conclusions: Compared to prostatectomy alone, prior treatment with salvage cryotherapy for recurrent prostate cancer was associated with an increased risk of AUS infection/erosion, whereas radiation (in addition to prostatectomy) was not.

Nanoscale Assembly in Biological Systems: From Neuronal Cytoskeletal Proteins to Curvature Stabilizing Lipids

Safinya, Cyrus R.,Raviv, Uri,Needleman, Daniel J.,Zidovska, Alexandra,Choi, Myung Chul,Ojeda‐,Lopez, Miguel A.,Ewert, Kai K.,Li, Youli,Miller, Herbert P.,Quispe, Joel,Carragher, Bridget,Potter, WILEY‐VCH Verlag 2011 ADVANCED MATERIALS Vol.23 No.20

<P><B>Abstract</B></P><P>The review will describe experiments inspired by the rich variety of bundles and networks of interacting microtubules (MT), neurofilaments, and filamentous‐actin in neurons where the nature of the interactions, structures, and structure‐function correlations remain poorly understood. We describe how three‐dimensional (3D) MT bundles and 2D MT bundles may assemble, in cell free systems in the presence of counter‐ions, revealing structures not predicted by polyelectrolyte theories. Interestingly, experiments reveal that the neuronal protein tau, an abundant MT‐associated‐protein in axons, modulates the MT diameter providing insight for the control of geometric parameters in bio‐ nanotechnology. In another set of experiments we describe lipid‐protein‐nanotubes, and lipid nano‐ tubes and rods, resulting from membrane shape evolution processes involving protein templates and curvature stabilizing lipids. Similar membrane shape changes, occurring in cells for the purpose of specific functions, are induced by interactions between membranes and proteins. The biological materials systems described have applications in bio‐nanotechnology.</P>

Treatment of In-Stent Stenosis Following Flow Diversion of Intracranial Aneurysms with Cilostazol and Clopidogrel

Ehsan Dowlati,Kory B. Dylan Pasko,Jiaqi Liu,Charles A. Miller,Daniel R. Felbaum,Samir Sur,Jason J. Chang,Ai-Hsi Liu,Rocco A. Armonda,Jeffrey C. Mai 대한신경중재치료의학회 2021 Neurointervention Vol.16 No.3

In-stent stenosis is a feared complication of flow diversion treatment for cerebral aneurysms. We present 2 cases of patients treated with pipeline flow diversion for unruptured cerebral aneurysms. Initial perioperative dual antiplatelet therapy (DAPT) consisted of standard aspirin plus clopidogrel. At 6-month follow-up cerebral angiography, the patients were noted to have developed significant in-stent stenosis (63% and 53%). The patients were treated with cilostazol and clopidogrel for at least 6 months. Subsequent angiography at 1-year post-treatment showed significant improvement of the in-stent stenosis from 63% to 34% and 53% to 21%. The role of cilostazol as treatment of intracranial in-stent stenosis has not been previously described. Cilostazol’s vasodilatory effect and suppression of vascular smooth muscle proliferation provides ideal benefits in this setting. Cilostazol plus clopidogrel may be a safe and effective alternative to standard DAPT for treatment of in-stent stenosis following flow diversion and warrants further consideration and investigation.

A bioinspired fouling-resistant surface modification for water purification membranes

McCloskey, Bryan D.,Park, Ho Bum,Ju, Hao,Rowe, Brandon W.,Miller, Daniel J.,Freeman, Benny D. Elsevier 2012 Journal of membrane science Vol.413 No.-

Mechanical Thrombectomy for Acute Ischemic Stroke in Metastatic Cancer Patients: A Nationwide Cross-Sectional Analysis

Hassan Aboul-Nour,Ahmed Maraey,Ammar Jumah,Mahmoud Khalil,Ahmed M. Elzanaty,Hadeer Elsharn,Fawaz Al-Mufti,Alex Bou Chebl,Daniel J. Miller,Stephan A. Mayer 대한뇌졸중학회 2023 Journal of stroke Vol.25 No.1

Background and Purpose Mechanical thrombectomy (MT) is the standard treatment for large vessel occlusion (LVO) acute ischemic stroke. Patients with active malignancy have an increased risk of stroke but were excluded from MT trials. Methods We searched the National Readmission Database for LVO patients treated with MT between 2016–2018 and compared the characteristics and outcomes of cancer-free patients to those with metastatic cancer (MC). Primary outcomes were all-cause in-hospital mortality and favorable outcome, defined as a routine discharge to home (regardless of whether home services were provided or not). Multivariate regression was used to adjust for confounders. Results Of 40,537 LVO patients treated with MT, 933 (2.3%) had MC diagnosis. Compared to cancer-free patients, MC patients were similar in age and stroke severity but had greater overall disease severity. Hospital complications that occurred more frequently in MC included pneumonia, sepsis, acute coronary syndrome, deep vein thrombosis, and pulmonary embolism (P<0.001). Patients with MC had similar rates of intracerebral hemorrhage (20% vs. 21%) but were less likely to receive tissue plasminogen activator (13% vs. 23%, P<0.001). In unadjusted analysis, MC patients as compared to cancer-free patients had a higher in-hospital mortality rate and were less likely to be discharged to home (36% vs. 42%, P=0.014). On multivariate regression adjusting for confounders, mortality was the only outcome that was significantly higher in the MC group than in the cancerfree group (P<0.001). Conclusion LVO patients with MC have higher mortality and more infectious and thrombotic complications than cancer-free patients. MT nonetheless can result in survival with good outcome in slightly over one-third of patients.