Publications by authors named "Alex Xu"

22 Publications

  • Page 1 of 1

Calibrated liposomal release of the anti-mitotic agent BI-2536 increases the targeting of mitotic tumor cells.

Eur J Pharm Biopharm 2020 Dec 22;157:183-190. Epub 2020 Oct 22.

Temasek Life Sciences Laboratory, Singapore; Department of Biological Sciences, National University of Singapore, Singapore. Electronic address:

Cancer drugs which are specifically targeted at mitosis have generally under-delivered as a class. One likely reason is that only a small percentage of cancer cells in a tumor are actually dividing at any moment. If this is the case, then prolonged bioavailability in the tumor should significantly increase the efficacy of antimitotic agents. Here, we show that if the Plk1 inhibitor BI 2536 is co-encapsulated in a liposome with a pair of anions, its release rate is dependent on both the identity and stoichiometry of the anions. We created a library of liposomes with varying release rates using this approach and found that liposomal drug release rates correlated inversely with in vitro cancer cell killing. Xenografted mice treated with a single dose of slow-releasing liposomal BI 2536 experienced tumor volume decreases lasting 12 days and complete responses in 20% of mice. Treatment with two doses a week apart increased the response rate to 75%. This approach, which we termed Paired Anion Calibrated Release (PACeR), has the potential to revive the clinical utility of antimitotic cancer drugs which have failed clinical trials.
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http://dx.doi.org/10.1016/j.ejpb.2020.10.006DOI Listing
December 2020

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

Cell 2020 12 28;183(6):1479-1495.e20. Epub 2020 Oct 28.

Institute for Systems Biology, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98105, USA. Electronic address:

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.
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http://dx.doi.org/10.1016/j.cell.2020.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598382PMC
December 2020

Hysteresis and Instability Predicted in Moisture Degradation of Perovskite Solar Cells.

ACS Appl Mater Interfaces 2020 Oct 15;12(43):48882-48889. Epub 2020 Oct 15.

Department of Materials Science and Engineering, McMaster University, Hamilton, Ontario, L8S4L8, Canada.

The degradation of the perovskite solar cell structure was expected recently to be reversible, which opened a new gate to the enhancement of the device lifetime by reversing the process. However, the kinetic details of the structural collapse and recovery are still missing, without which the perovskite reversibility cannot be further explored. Due to the experimental difficulty, a purposeful numerical model was conducted in this report, to simulate the water diffusion process in the perovskite structure in both directions. It was found that the moisture diffusion needs to be initiated by a certain level of structural imperfection and is non-Fickian, as assisted by the collapse of the perovskite into the 1D chains. The reversibility was verified by the back diffusion, but accompanied by hysteresis, stagnancy, and even surprising instability, which initiated the water flow under initial equilibrium, due possibly to the imbalance during the reconstruction of the perovskite lattice. These observations offer new insights to form strategies of improvement, for example, via the possible self-healing perovskite devices.
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http://dx.doi.org/10.1021/acsami.0c17323DOI Listing
October 2020

The New PGY-1 Year: Lessons Learned.

Curr Urol Rep 2020 Aug 19;21(10):42. Epub 2020 Aug 19.

Department of Urology, New York University Grossman School of Medicine, 222 East 41st, 12th floor, New York, NY, 10017, USA.

Purpose Of Review: Describe the ACGME's changes to the PGY-1 year in urology and discuss the benefits and challenges faced by training programs.

Recent Findings: There are no publications detailing the integration of the PGY-1 year in urology; however, response of other surgical subspecialties to their own integration has been studied. Benefits of integration include earlier exposure to techniques and knowledge specific to urology, potentially leading to increased preparedness for next steps in training and exams. Program directors have more flexibility to select rotations relevant to urology. Resident wellness may be improved as interns are incorporated into the department earlier and can help distribute the workload for senior residents. Challenges include decreased exposure to basic surgical knowledge and skills, decreased camaraderie with general surgery colleagues, and difficulties associated with evaluating interns who are spending limited time with urology departments. Overall, the change seems to have a positive impact on urological training.
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http://dx.doi.org/10.1007/s11934-020-00996-xDOI Listing
August 2020

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories.

bioRxiv 2020 Jul 31. Epub 2020 Jul 31.

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8 and CD4 T cells, and cytotoxic CD4 T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.
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http://dx.doi.org/10.1101/2020.07.27.224063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402042PMC
July 2020

A Multi-Institutional Experience With Robotic Appendiceal Ureteroplasty.

Urology 2020 Nov 15;145:287-291. Epub 2020 Jul 15.

Department of Urology, New York University Grossman School of Medicine at New York University Langone Medical Center, New York, NY. Electronic address:

Objective: To report a multi-institutional experience with robotic appendiceal ureteroplasty.

Methods: This is a retrospective review of 13 patients undergoing right appendiceal flap ureteroplasty at 2 institutions between April 2016 and October 2019. The primary endpoint was surgical success defined by the absence of flank pain and radiographic evidence of ureteral patency.

Results: Eight of 13 (62%) underwent appendiceal onlay while 5/13 (38%) underwent appendiceal interposition. Mean length of stricture was 6.5 cm (range 1.5-15 cm) affecting anywhere along the right ureter. Mean operative time was 337 minutes (range 206-583), mean estimated blood loss was 116 mL (range 50-600), and median length of stay was 2.5 days (range 1-9). Balloon dilation was required in 1/12 (8%). One patient died on postoperative day 0 due to a sudden cardiovascular event. Otherwise, there were no complications (Clavien-Dindo > 2) within 30 days from surgery. At a mean follow up of 14.6 months, 11/12 (92%) were successful.

Conclusion: Robotic appendiceal ureteroplasty for right ureteral strictures is a versatile technique with high success rates across institutions.
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http://dx.doi.org/10.1016/j.urology.2020.06.062DOI Listing
November 2020

Achieving Nonenzymatic Blood Glucose Sensing by Uprooting Saturation.

Anal Chem 2020 08 22;92(15):10777-10782. Epub 2020 Jul 22.

Department of Materials Science and Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.

The saturation of nonenzymatic blood glucose sensors at lower than normal blood glucose levels has blocked their practical applications. The mechanistic understanding of the saturation, however, has long been under debate. Employing cyclic voltammetry, amperometry, and FTIR with various electrolytes of varying concentrations, we were able to uproot the saturation cause. It was found to be related to the hydroxide ion concentration, which must be 11 times greater than that of the glucose concentration, contrary to the prior understanding. Together with the satisfactory sensitivity at high pH, nonenzymatic blood glucose sensing has finally been achieved, eliminating the usual problem of electrochemical current saturation as well as the need for enzyme found in the present technology.
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http://dx.doi.org/10.1021/acs.analchem.0c02218DOI Listing
August 2020

Promoting Thermodynamic and Kinetic Stabilities of FA-based Perovskite by an in Situ Bilayer Structure.

Nano Lett 2020 May 4;20(5):3864-3871. Epub 2020 May 4.

Department of Materials Science and Engineering, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

The commonly employed formamidinium (FA)-containing perovskite solar cells (PSCs) exhibit a severe phase instability problem, thereby limiting their commercial applications. Here, both phase stability and energy efficiency of FA-based PSCs were improved by treating the perovskite surface with pyrrolidinium hydroiodide (PyI) salts, resulting in a 1D perovskite structure (PyPbI), stacked on the original 3D perovskite. By employing in situ XRD measurements, we revealed that the temperature-dependent phase transition activation barrier was enhanced after forming the 1D/3D structure, resulting in a prolonged transition time by 30-40-fold. From the first-principle calculations, we found the thermodynamic energy difference between two phases reduced from -0.16 to -0.04 eV after the stacking of 1D PyPbI, offering additional lifetime improvement. Moreover, the champion 1D/3D bilayer PSC exhibits a boosted power conversion efficiency of 19.62%, versus 18.21% of the control. Such 1D/3D bilayer structure may be employed in PSCs to enhance their phase stability and photovoltaic performance.
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http://dx.doi.org/10.1021/acs.nanolett.0c00988DOI Listing
May 2020

Regulatory landscape of dietary supplements and herbal medicines from a global perspective.

Regul Toxicol Pharmacol 2020 Jul 16;114:104647. Epub 2020 Apr 16.

National Center for Toxicological Research (NCTR), Food and Drug Administration (FDA), USA. Electronic address:

The number of Individuals that use dietary supplements and herbal medicine products are continuous to increase in many countries. The context of usage of a dietary supplement varies widely from country-to-country; in some countries supplement use is just limited to general health and well-being while others permit use for medicinal purposes. To date, there is little consensus from country to country on the scope, requirements, definition, or even the terminology in which dietary supplement and herbal medicines categories could be classified. Transparent science-based quality standards for the ingredients across these regulatory frameworks/definitions becomes even more important given the international supply chain. Meanwhile, there has been a rapid advancement in emerging technologies and data science applied to the field. This review was conceived at the Global Summit on Regulatory Sciences that took place in Beijing on September 2018 (GSRS2018) which is organized by Global Coalition for Regulatory Science Research (GCRSR) that consists of the global regulatory agencies from over ten countries including the European Union. This review summarizes a significant portion of discussions relating to a longitudinal comparison of the status for dietary supplements and herbal medicines among the different national jurisdictions and to the extent of how new tools and methodologies can improve the regulatory application.
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http://dx.doi.org/10.1016/j.yrtph.2020.104647DOI Listing
July 2020

Reversing Organic-Inorganic Hybrid Perovskite Degradation in Water via pH and Hydrogen Bonds.

J Phys Chem Lett 2019 Nov 11;10(22):7245-7250. Epub 2019 Nov 11.

MAX Diffraction Facility, Department of Chemistry , McMaster University , 1280 Main Street West , Hamilton , Ontario L8S 4M1 , Canada.

The moisture instability of organic-inorganic hybrid perovskite solar cells has been a major obstacle to the commercialization, calling for mechanistic understanding of the degradation process, which has been under debate. Here we present a surprising discovery that the degradation is actually reversible, via in situ observation of X-ray diffraction, supported by FTIR and SEM. To isolate the hydrogen bond effect, water was replaced by methanol during the in situ experiment, revealing the decomposition to be initiated by the breakdown of N-H-I hydrogen bonds. This is followed by the step of organic iodide hydrolyzing, which can be inhibited in the neutral environment, making the whole process reversible under variable pH.
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http://dx.doi.org/10.1021/acs.jpclett.9b02972DOI Listing
November 2019

Pyrrolidinium lead iodide from crystallography: a new perovskite with low bandgap and good water resistance.

Chem Commun (Camb) 2019 Mar;55(22):3251-3253

Department of Materials Science and Engineering, McMaster University, 1280 Main ST W, Hamilton, ON, L8S 4L8 Canada.

The crystal structure of a new perovskite material, (C4H8NH2)PbI3 was determined and illustrated by single crystal X-ray diffraction. UV spectra, photoluminescence and XRD results show it is a promising alternative to hybrid organic-inorganic perovskites due to it's good water resistance and suitable bandgap.
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http://dx.doi.org/10.1039/c8cc10135cDOI Listing
March 2019

Long-term Natural History of Lower Urinary Tract Symptoms Following Radical Retropubic Prostatectomy: A Prospective 15-Year Longitudinal Study.

Urology 2018 Oct 25;120:167-172. Epub 2018 Jun 25.

Department of Urology, New York University School of Medicine, New York, NY. Electronic address:

Objective: To provide insights into the long-term impact of radical retro-pubic prostatectomy (ORRP) on lower urinary tract symptoms (LUTS) which are age and prostate dependent and adversely impact quality of life.

Methods: 1995 men undergoing ORRP enrolled in a prospective longitudinal outcomes study. The American Urological Association Symptom Index was self-administered before ORRP and at predetermined time-points after surgery. A multivariate generalized linear model was used to evaluate the association of time since ORRP with American Urological Association symptom score (AUASS). McNemar's test and paired sample t-tests were used to assess whether the proportion of men with clinically significant LUTS (CSLUTS) defined by an AUASS >7 or mean AUASS differed significantly between the time-dependent assessments, respectively.

Results: The 15-year mean adjusted AUASS was similar to baseline (7.00 vs 6.85, P = .66). Throughout the 15 years of follow-up, the proportion of men with CSLUTS was lower than baseline with the exception of the 3 month and 15 year assessments. Among men with baseline clinically insignificant LUTS (CILUTS), the mean adjusted AUASS at 15 years was significantly greater than baseline (6.09 vs 3.19, P < .001). Among men with baseline CSLUTS, ORRP led to a significant decrease in mean adjusted AUASS between baseline and 15 years (13.26 vs 8.67, P < .001).

Conclusion: ORRP favorably affects the long-term natural history of LUTS. The long-term economic and quality of life benefits of ORRP on LUTS should inform the risks and benefits of RP for treatment of localized prostate cancer.
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http://dx.doi.org/10.1016/j.urology.2018.06.014DOI Listing
October 2018

Long-Term Continence Outcomes in Men Undergoing Radical Prostatectomy: A Prospective 15-Year Longitudinal Study.

J Urol 2018 09 7;200(3):626-632. Epub 2018 May 7.

Department of Urology, New York University School of Medicine, New York, New York. Electronic address:

Purpose: We examined the time dependent rates of urinary continence following open retropubic radical prostatectomy.

Materials And Methods: A total of 1,995 men treated with radical prostatectomy were enrolled in a prospective longitudinal outcomes study. The UCLA-PCI-UFS (UCLA-Prostate Cancer Index-Urinary Function Index) was administered at baseline, and 3, 6, 12, 24, 96, 120 and 180 months after open retropubic radical prostatectomy. Urinary continence was defined by 1 pad or less in 24 hours. Two multiple regression models were constructed to evaluate the association of time since open retropubic radical prostatectomy with the UCLA-PCI-UFI score and urinary continence.

Results: The decrease in urinary continence rates between baseline and 15 years (99.6% vs 87.2%, p <0.001), and 2 and 15 years (95.3% vs 87.2%, p = 0.021) were statistically significant. Urinary continence rates were consistently higher in the younger group at all time points.

Conclusions: A significant decrease in urinary continence rates was observed between baseline and 2 years, and between 2 and 15 years in the entire cohort. Urinary continence rates in age matched men in the general population who were followed longitudinally for 15 years were comparable to those in our study population. This suggests that while open retropubic radical prostatectomy causes primarily sphincteric urinary incontinence, it may be protective for subsequent benign prostatic hyperplasia mediated urinary incontinence.
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http://dx.doi.org/10.1016/j.juro.2018.05.005DOI Listing
September 2018

HistoScanning to Detect and Characterize Prostate Cancer-a Review of Existing Literature.

Curr Urol Rep 2017 Oct 24;18(12):97. Epub 2017 Oct 24.

Division of Urologic Oncology, Department of Urology, New York University Langone Medical Center, New York, NY, USA.

Purpose Of Review: The widely acknowledged limitations of the standard prostate cancer (PCa) diagnostic paradigm have provided an impetus to explore novel imaging modalities to diagnose, localize, and risk stratify PCa. As the body of literature focused on HistoScanning™(HS) grows, there is need for a comprehensive review of the clinical efficacy of this technology.

Recent Findings: Eighteen original, English language articles were found to adequately study the use of HistoScanning™ for prostate cancer diagnosis in the clinical setting. The articles were found by conducting a bibliographic search of PubMed in April 2017 in addition to utilizing references. The studies are divided into four groups based on study design. Study methods and quantitative data are summarized for each of the relevant articles. The results are synthesized to evaluate the utility of HistoScanning™ for the purpose of diagnosing PCa. Despite the promise of early pilot studies, there is a lack of consistent results across a number of further investigations of HistoScanning™. This becomes increasingly evident as study size increases. As various other modern diagnostic modalities continue to develop, the future of HistoScanning™, both alone and in conjunction with these technologies, remains unclear.
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http://dx.doi.org/10.1007/s11934-017-0747-yDOI Listing
October 2017

Brain Injury and Inflammatory Response to Umbilical Cord Occlusions Is Limited With Worsening Acidosis in the Near-Term Ovine Fetus.

Reprod Sci 2016 07 23;23(7):858-70. Epub 2015 Dec 23.

Department of Obstetrics and Gynecology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening fetal acidemia will lead to an inflammatory response within the brain and thereby brain injury which will be exacerbated by chronic hypoxemia and low-grade infection. Chronically instrumented fetal sheep served as controls (N = 10) or underwent repeated UCOs for up to 4 hours or until arterial pH was <7.00. Normoxic-UCO (N = 9) and hypoxic-UCO (N = 5) fetuses had arterial O2 saturation pre-UCOs of >55% and <55%, respectively, whereas lipopolysaccharide (LPS) UCO fetuses (N = 6) received LPS intra-amniotic (2 mg/h) starting 1 hour pre-UCOs. Animals were euthanized at 48 hours of recovery with fetal brains processed for assessment of inflammation (microglia and mast cell counts) and injury (necrosis-hematoxylin and eosin-and apoptosis-cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]). Repetitive UCOs resulted in severe acidemia in most animals with pH approaching 7.00 for all 3 UCO groups. However, there was no significant effect on measures of brain inflammation or injury, except in the LPS-UCO animals where TUNEL-positive cells were increased in the hippocampus, although small animal numbers in the hypoxic-UCO group may have limited the ability to detect significance in their TUNEL cell findings. We were therefore unable to confirm our working hypothesis since the near-term ovine fetal brain showed remarkable tolerance for these cord occlusion insults and likely involving protective metabolic mechanisms, despite the severe acidemia noted.
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http://dx.doi.org/10.1177/1933719115623640DOI Listing
July 2016

The Ovine Fetal and Placental Inflammatory Response to Umbilical Cord Occlusions With Worsening Acidosis.

Reprod Sci 2015 Nov 15;22(11):1409-20. Epub 2015 Apr 15.

Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada

We hypothesized that repetitive umbilical cord occlusions (UCOs) leading to severe acidemia will stimulate a placental and thereby fetal inflammatory response which will be exacerbated by chronic hypoxemia and low-grade bacterial infection. Chronically instrumented fetal sheep served as controls or underwent repetitive UCOs for up to 4 hours or until fetal arterial pH was <7.00. Normoxic-UCO and hypoxic-UCO fetuses had arterial O2 saturation pre-UCOs of >55% and <55%, respectively, while lipopolysaccharide (LPS)-UCO fetuses received LPS intra-amniotic (2 mg/h) starting 1 hour pre-UCOs. Fetal plasma and amniotic fluid were sampled for interleukin (IL) 6 and IL-1β. Animals were euthanized at 48 hours of recovery with placental cotyledons processed for measurement of macrophage, neutrophil, and mast cell counts. Repetitive UCOs resulted in severe fetal acidemia with pH approaching 7.00 for all 3 UCO groups. Neutrophils, while unchanged within the cotyledon fetal and intermediate zones, were ∼2-fold higher within the zona intima for all 3 UCO groups. However, no differences were observed in macrophage counts among the treatment groups and no cotyledon mast cells were seen. Fetal plasma and amniotic fluid cytokines remained little changed post-UCOs and/or at 1 and 48 hours of recovery in the normoxic-UCO and hypoxic-UCO groups but increased several fold in the LPS-UCO group with IL-6 plasma values at 1 hour recovery highly correlated with the nadir pH attained (r = -.97). As such, repetitive UCOs with severe acidemia can induce a placental inflammatory response and more so with simulated low-grade infection and likely contributing to cytokine release in the umbilical circulation.
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http://dx.doi.org/10.1177/1933719115580994DOI Listing
November 2015

Adaptive brain shut-down counteracts neuroinflammation in the near-term ovine fetus.

Front Neurol 2014 30;5:110. Epub 2014 Jun 30.

Department of Obstetrics and Gynaecology and Department of Neurosciences, CHU Sainte-Justine Centre de Recherche, Université de Montréal , Montréal, QC , Canada.

Objective: Repetitive umbilical cord occlusions (UCOs) in ovine fetus leading to severe acidemia result in adaptive shut-down of electrocortical activity [electrocorticogram (ECoG)] as well as systemic and brain inflammation. We hypothesized that the fetuses with earlier ECoG shut-down as a neuroprotective mechanism in response to repetitive UCOs will show less brain inflammation and, moreover, that chronic hypoxia will impact this relationship.

Methods: Near-term fetal sheep were chronically instrumented with ECoG leads, vascular catheters, and a cord occluder and then underwent repetitive UCOs for up to 4 h or until fetal arterial pH was <7.00. Eight animals, hypoxic prior to the UCOs (SaO2 <55%), were allowed to recover 24 h post insult, while 14 animals, 5 of whom also were chronically hypoxic, were allowed to recover 48 h post insult, after which brains were perfusion-fixed. Time of ECoG shut-down and corresponding pH were noted, as well as time to then reach pH <7.00 (ΔT). Microglia (MG) were counted as a measure of inflammation in gray matter layers 4-6 (GM4-6) where most ECoG activity is generated. RESULTS are reported as mean ± SEM for p < 0.05.

Results: Repetitive UCOs resulted in worsening acidosis over 3-4 h with arterial pH decreasing to 6.97 ± 0.02 all UCO groups' animals, recovering to baseline by 24 h. ECoG shut-down occurred 52 ± 7 min before reaching pH <7.00 at pH 7.23 ± 0.02 across the animal groups. MG counts were inversely correlated to ΔT in 24 h recovery animals (R = -0.84), as expected. This was not the case in normoxic 48 h recovery animals, and, surprisingly, in hypoxic 48 h recovery animals, this relationship was reversed (R = 0.90).

Conclusion: Adaptive brain shut-down during labor-like worsening acidemia counteracts neuroinflammation in a hypoxia- and time-dependent manner.
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http://dx.doi.org/10.3389/fneur.2014.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074896PMC
July 2014

Production of hydrogen using nanocrystalline protein-templated catalysts on m13 phage.

ACS Nano 2010 Jun;4(6):3227-35

Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

For decades, ethanol has been in use as a fuel for the storage of solar energy in an energy-dense, liquid form. Over the past decade, the ability to reform ethanol into hydrogen gas suitable for a fuel cell has drawn interest as a way to increase the efficiency of both vehicles and stand-alone power generators. Here we report the use of extremely small nanocrystalline materials to enhance the performance of 1% Rh/10% Ni@CeO(2) catalysts in the oxidative steam reforming of ethanol with a ratio of 1.7:1:10:11 (air/EtOH/water/argon) into hydrogen gas, achieving 100% conversion of ethanol at only 300 degrees C with 60% H(2) in the product stream and less than 0.5% CO. Additionally, nanocrystalline 10% Ni@CeO(2) was shown to achieve 100% conversion of ethanol at 400 degrees C with 73% H(2), 2% CO, and 2% CH(4) in the product stream. Finally, we demonstrate the use of biological templating on M13 to improve the resistance of this catalyst to deactivation over 52 h tests at high flow rates (120 000 h(-1) GHSV) at 450 degrees C. This study suggests that the use of highly nanocrystalline, biotemplated catalysts to improve activity and stability is a promising route to significant gains over traditional catalyst manufacture methods.
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http://dx.doi.org/10.1021/nn100346hDOI Listing
June 2010

Mode of action: disruption of brain cell replication, second messenger, and neurotransmitter systems during development leading to cognitive dysfunction--developmental neurotoxicity of nicotine.

Crit Rev Toxicol 2005 Oct-Nov;35(8-9):703-11

Division of Neurotoxicology, NCTR/FDA, Jefferson, Arkansas 72079, USA.

Developmental exposure to nicotine in rats results in neurobehavioral effects such as reduced locomotor and cognitive function. Key events in the animal mode of action (MOA) include binding to the nicotinic cholinergic receptor during prenatal and/or early postnatal development. This leads to premature onset of cell differentiation at the expense of cell replication, which leads to brain cell death or structural alterations in regional brain areas. Other events include an initial increase followed by a decrease in adenyl cyclase activity, as well as effects on the noradrenergic, dopaminergic, and serotonergic neurotransmitter systems. Because the nicotine receptor is also present in the developing human brain and the underlying biology for DNA synthesis and cell signaling is comparable, this MOA is likely to be relevant for humans. Although the effects of nicotine exposure in developing humans is not well documented, nicotine exposure as a result of cigarette smoking during pregnancy is associated with several physiological and behavioral outcomes that are reminiscent of the effects of nicotine alone in animal models. As data become available with the advent of the use of the nicotine patch in pregnant humans, the question as to the relative importance of smoking per se versus nicotine alone may be determined.
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http://dx.doi.org/10.1080/10408440591007421DOI Listing
February 2006

Cross-platform comparability of microarray technology: intra-platform consistency and appropriate data analysis procedures are essential.

BMC Bioinformatics 2005 Jul 15;6 Suppl 2:S12. Epub 2005 Jul 15.

National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.

Background: The acceptance of microarray technology in regulatory decision-making is being challenged by the existence of various platforms and data analysis methods. A recent report (E. Marshall, Science, 306, 630-631, 2004), by extensively citing the study of Tan et al. (Nucleic Acids Res., 31, 5676-5684, 2003), portrays a disturbingly negative picture of the cross-platform comparability, and, hence, the reliability of microarray technology.

Results: We reanalyzed Tan's dataset and found that the intra-platform consistency was low, indicating a problem in experimental procedures from which the dataset was generated. Furthermore, by using three gene selection methods (i.e., p-value ranking, fold-change ranking, and Significance Analysis of Microarrays (SAM)) on the same dataset we found that p-value ranking (the method emphasized by Tan et al.) results in much lower cross-platform concordance compared to fold-change ranking or SAM. Therefore, the low cross-platform concordance reported in Tan's study appears to be mainly due to a combination of low intra-platform consistency and a poor choice of data analysis procedures, instead of inherent technical differences among different platforms, as suggested by Tan et al. and Marshall.

Conclusion: Our results illustrate the importance of establishing calibrated RNA samples and reference datasets to objectively assess the performance of different microarray platforms and the proficiency of individual laboratories as well as the merits of various data analysis procedures. Thus, we are progressively coordinating the MAQC project, a community-wide effort for microarray quality control.
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http://dx.doi.org/10.1186/1471-2105-6-S2-S12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637032PMC
July 2005

Microarray scanner calibration curves: characteristics and implications.

BMC Bioinformatics 2005 Jul 15;6 Suppl 2:S11. Epub 2005 Jul 15.

National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.

Background: Microarray-based measurement of mRNA abundance assumes a linear relationship between the fluorescence intensity and the dye concentration. In reality, however, the calibration curve can be nonlinear.

Results: By scanning a microarray scanner calibration slide containing known concentrations of fluorescent dyes under 18 PMT gains, we were able to evaluate the differences in calibration characteristics of Cy5 and Cy3. First, the calibration curve for the same dye under the same PMT gain is nonlinear at both the high and low intensity ends. Second, the degree of nonlinearity of the calibration curve depends on the PMT gain. Third, the two PMTs (for Cy5 and Cy3) behave differently even under the same gain. Fourth, the background intensity for the Cy3 channel is higher than that for the Cy5 channel. The impact of such characteristics on the accuracy and reproducibility of measured mRNA abundance and the calculated ratios was demonstrated. Combined with simulation results, we provided explanations to the existence of ratio underestimation, intensity-dependence of ratio bias, and anti-correlation of ratios in dye-swap replicates. We further demonstrated that although Lowess normalization effectively eliminates the intensity-dependence of ratio bias, the systematic deviation from true ratios largely remained. A method of calculating ratios based on concentrations estimated from the calibration curves was proposed for correcting ratio bias.

Conclusion: It is preferable to scan microarray slides at fixed, optimal gain settings under which the linearity between concentration and intensity is maximized. Although normalization methods improve reproducibility of microarray measurements, they appear less effective in improving accuracy.
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http://dx.doi.org/10.1186/1471-2105-6-S2-S11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637029PMC
July 2005

Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine.

Ann N Y Acad Sci 2004 Oct;1025:267-73

Research and Development, Sigma-tau HealthScience S.p.A., Pomezia 00040, Italy.

The damage to the central nervous system that is observed after administration of either methamphetamine (METH) or 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to be linked to dopamine (DA). The underlying neurotoxicity mechanism for both METH and MPP+ seem to involve free radical formation and impaired mitochondrial function. The MPP+ is thought to selectively kill nigrostriatal dopaminergic neurons by inhibiting mitochondrial complex I, with cell death being attributed to oxidative stress damage to these vulnerable DA neurons. In the present study, MPP+ was shown to significantly inhibit the response to MTT by cultured PC12 cells. This inhibitory action of MPP+ could be partially reversed by the co-incubation of the cells with the acetylated form of carnitine, acetyl-L-carnitine (ALC). Since at least part of the toxic action of MPP+ is related to mitochondrial inhibition, the partial reversal of the inhibition of MTT response by ALC could involve a partial restoration of mitochondrial function. The role carnitine derivatives, such as ALC, play in attenuating MPP+ and METH-evoked toxicity is still under investigation to elucidate the contribution of mitochondrial dysfunction in mechanisms of neurotoxicity.
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http://dx.doi.org/10.1196/annals.1316.033DOI Listing
October 2004