29 results on '"Conley, Nicholas"'
Search Results
2. Social Determinants of Health, Chronic Disease Management, and the Role of the Primary Care Provider—to Include Cardiovascular Disease, Cancer, Diabetes, Major Causes of Morbidity and Mortality as Affected by Social Determinants of Health
- Author
-
Conley, Nicholas
- Published
- 2023
- Full Text
- View/download PDF
3. Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.
- Author
-
Purzner, Teresa, Purzner, James, Buckstaff, Taylor, Cozza, Giorgio, Gholamin, Sharareh, Rusert, Jessica, Hartl, Tom, Sanders, John, Conley, Nicholas, Ge, Xuecai, Langan, Marc, Ramaswamy, Vijay, Ellis, Lauren, Litzenburger, Ulrike, Bolin, Sara, Theruvath, Johanna, Nitta, Ryan, Qi, Lin, Li, Xiao-Nan, Li, Gordon, Taylor, Michael, Wechsler-Reya, Robert, Pinna, Lorenzo, Cho, Yoon-Jae, Fuller, Margaret, Elias, Joshua, and Scott, Matthew
- Subjects
Anilides ,Animals ,Casein Kinase II ,Cell Line ,Tumor ,Cerebellar Neoplasms ,Gene Expression Regulation ,Neoplastic ,Hedgehog Proteins ,Humans ,Kaplan-Meier Estimate ,Medulloblastoma ,Mice ,Mice ,Inbred NOD ,Mice ,Knockout ,Mice ,Nude ,Mice ,SCID ,NIH 3T3 Cells ,Naphthyridines ,Neoplasms ,Experimental ,Phenazines ,Phosphoproteins ,Proteomics ,Pyridines ,Signal Transduction ,Xenograft Model Antitumor Assays - Abstract
A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.
- Published
- 2018
4. Meta-analysis of primary care delivered buprenorphine treatment retention outcomes.
- Author
-
Cooper, Robert L., Edgerton, Ryan D., Watson, Julia, Conley, Nicholas, Agee, William A., Wilus, Derek M., MacMaster, Samuel A., Bell, Lisa, Patel, Parul, Godbole, Amruta, Bass-Thomas, Cynthia, Ramesh, Aramandla, and Tabatabai, Mohammad
- Subjects
OPIOID abuse ,PRIMARY care ,BUPRENORPHINE ,RACE ,RF values (Chromatography) - Abstract
Background: Currently, the capacity to provide buprenorphine treatment (BT) is not sufficient to treat the growing number of people in the United States with opioid use disorder (OUD). We sought to examine participant retention in care rates of primary care delivered BT programs and to describe factors associated with retention/attrition for participants receiving BT in this setting. Objectives: A PRISMA-guided search of various databases was performed to identify the articles focusing on efficacy of BT treatment and OUD. Method: A systematic literature search identified 15 studies examining retention in care in the primary care setting between 2002 and 2020. Random effects meta-regression were used to identify retention rates across studies. Results: Retention rates decreased across time with a mean 0.52 rate at one year. Several factors were found to be related to retention, including: race, use of other drugs, receipt of counseling, and previous treatment with buprenorphine. Conclusions: While we only investigate BT through primary care, our findings indicate retention rates are equivalent to the rates reported in the specialty care literature. More work is needed to examine factors that may impact primary care delivered BT specifically and differentiate participants that may benefit from care delivered in specialty over primary care as well as the converse. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Sensing cooperativity in ATP hydrolysis for single multisubunit enzymes in solution
- Author
-
Jiang, Yan, Douglas, Nicholai R., Conley, Nicholas R., Miller, Erik J., Frydman, Judith, and Moerner, W. E.
- Published
- 2011
6. Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma
- Author
-
Hayden Gephart, Melanie G., Su, YouRong Sophie, Bandara, Samuel, Tsai, Feng-Chiao, Hong, Jennifer, Conley, Nicholas, Rayburn, Helen, Milenkovic, Ljiljana, Meyer, Tobias, and Scott, Matthew P.
- Published
- 2013
- Full Text
- View/download PDF
7. Genetic and Functional Assessment of the Role of the rs13431652-A and rs573225-A Alleles in the G6PC2 Promoter That Are Strongly Associated With Elevated Fasting Glucose Levels
- Author
-
Bouatia-Naji, Nabila, Bonnefond, Amélie, Baerenwald, Devin A., Marchand, Marion, Bugliani, Marco, Marchetti, Piero, Pattou, François, Printz, Richard L., Flemming, Brian P., Umunakwe, Obi C., Conley, Nicholas L., Vaxillaire, Martine, Lantieri, Olivier, Balkau, Beverley, Marre, Michel, Lévy-Marchal, Claire, Elliott, Paul, Jarvelin, Marjo-Riitta, Meyre, David, Dina, Christian, Oeser, James K., Froguel, Philippe, and OʼBrien, Richard M.
- Published
- 2010
- Full Text
- View/download PDF
8. A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States.
- Author
-
Sanderson, Maureen, Pal, Tuya, Beeghly-Fadiel, Alicia, Fadden, Mary Kay, Dujon, Steffie-Ann, Clinton, Chrystina, Jimenez, Cecilia, Davis, Jennifer, Fortune, Mieke, Thompson, Jasmine, Benson, Kiera, Conley, Nicholas, Reid, Sonya, Tezak, Ann, Xiao-Ou Shu, Wei Zheng, Blot, William J., and Lipworth, Loren
- Abstract
Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors. Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2+ and triple-negative breast cancer (TNBC) status in relation to estrogen receptor-positive (ER+)/HER2- status (referent) for reproductive risk factors. Results: Relative to women who had ER+/HER2- tumors, women who were age 19-24 years at first birth (OR, 1.78; 95% CI, 1.22-2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2+ breast cancer and more likely to be diagnosed with TNBC relative to ER+/HER2- breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43-0.99)]. Conclusions: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes. Impact: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER+/HER2- breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
9. The Property-Based Practical Applications and Solutions of Genetically Encoded Acetylcholine and Monoamine Sensors.
- Author
-
Jun Chen, Cho, Katriel E., Skwarzynska, Daria, Clancy, Shaylyn, Conley, Nicholas J., Clinton, Sarah M., Xiaokun Li, Li Lin, and Zhu, J. Julius
- Subjects
ACETYLCHOLINE ,DETECTORS ,ALZHEIMER'S disease ,NEURAL transmission - Abstract
Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. In vitro and in vivo experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter sensors in expanding our knowledge of various behaviors and diseases, including Alzheimer’s disease, sleeping disorders, tumorigenesis, and many others. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
10. Azido push-pull fluorogens photoactivate to produce bright fluorescent labels
- Author
-
Lord, Samuel J., Lee, Hsiao-lu D., Samuel, Reichel, Weber, Ryan, Liu, Na, Conley, Nicholas R., Thompson, Michael A., Twieg, Robert J., and Moerner, W. E.
- Subjects
Charge transfer -- Analysis ,Azides -- Electric properties ,Azides -- Chemical properties ,Chemicals, plastics and rubber industries - Published
- 2010
11. Cy3-Cy5 covalent heterodimers for single-molecule photoswitching
- Author
-
Conley, Nicholas R., Biteen, Julie S., and Moerner, W.E.
- Subjects
Carbon compounds -- Chemical properties ,Carbon compounds -- Electric properties ,Chemicals, plastics and rubber industries - Abstract
The commercially available starting materials were used to characterize the covalent heterodimers of the Cy3 and Cy5 fluorophores at the single-molecule level. The covalent Cy3-Cy5 heterodimers were found to eliminate the need for probabilistic methods of situating the Cy3 and Cy5 in close proximity to enable photoswitching.
- Published
- 2008
12. A photoactivatable push-pull fluorophore for single-molecule imaging in live cells
- Author
-
Lord, Samuel J., Conley, Nicholas R., Lee, Hsiao-Iu D., Samuel, Reichel, Na Liu, Twieg, Robert J., and Moerner, W.E.
- Subjects
Photochemistry -- Analysis ,Absorption -- Analysis ,Molecular mechanics -- Analysis ,Chemistry - Abstract
A new, bright photoactivatable organic fluorophore is described that can be imaged at the single-molecule level in living cells. The azido-DCDHF fluorogen is an example of a rich new class of photoactivatable molecules, which is a powerful tool for single-molecule studies in the chemically and optically complex medium of the cell.
- Published
- 2008
13. Bulk and single-molecule characterization of an improved molecular beacon utilizing H-dimer excitonic behavior
- Author
-
Conley, Nicholas R., Pomerantz, Andrea Kurtz, Hui Wang, Twieg, Robert J., and Moerner, W.E.
- Subjects
Fluorescence -- Analysis ,Furans -- Structure ,Furans -- Chemical properties ,Furans -- Optical properties ,Methyl groups -- Structure ,Methyl groups -- Chemical properties ,Methyl groups -- Optical properties ,Bleaching -- Analysis ,Chemicals, plastics and rubber industries - Abstract
A pair of fluorophores in the new dicyanomethylenedihydrofuran (DCDHF) dye family was used to design and characterize a new fluorescent probe for nucleic acid detection, referred as a self-quenched intramolecular dimer (SQuID) molecular beacon (MB).
- Published
- 2007
14. Methanol
- Author
-
Luttrell, William E. and Conley, Nicholas L.
- Published
- 2011
- Full Text
- View/download PDF
15. A Selenium Analogue of Firefly D-Luciferin with Red-Shifted Bioluminescence Emission.
- Author
-
Conley, Nicholas R., Dragulescu-Andrasi, Anca, Rao, Jianghong, and Moerner, W. E.
- Published
- 2012
- Full Text
- View/download PDF
16. Palladium-Catalyzed Carbonylation of Diols to Cyclic Carbonates.
- Author
-
Pearson, David M., Conley, Nicholas R., and Waymouth, Robert M.
- Published
- 2011
- Full Text
- View/download PDF
17. Sensing cooperativity in ATP hydrolysis for single multisubunit enzymes in solution.
- Author
-
Yan Jiang, Douglas, Nicholai R., Conley, Nicholas R., Miller, Erik J., Frydman, Judith, and Moerner, W. E.
- Subjects
ADENOSINE triphosphate ,HYDROLYSIS ,ENZYME analysis ,MOLECULAR chaperones ,NUCLEOTIDE analysis ,BROWNIAN motors - Abstract
In order to operate in a coordinated fashion, multisubunit enzymes use cooperative interactions intrinsic to their enzymatic cycle, but this process remains poorly understood. Accordingly, ATP number distributions in various hydrolyzed states have been obtained for single copies of the mammalian double-ring multisubunit chaperonin TRiC/CCT in free solution using the emission from chaperonin-bound fluorescent nucleotides and closed-loop feedback trapping provided by an Anti-Brownian ELectrokinetic trap. Observations of the 16-subunit complexes as ADP molecules are dissociating shows a peak in the bound ADP number distribution at 8 ADP, whose height falls over time with little shift in the position of the peak, indicating a highly cooperative ADP release process which would be difficult to observe by ensemble-averaged methods. When AlFx is added to produce ATP hydrolysis transition state mimics (ADP·AlFx) locked to the complex, the peak at 8 nucleotides dominates for all but the lowest incubation concentrations. Although ensemble averages of the single-molecule data show agreement with standard cooperativity models, surprisingly, the observed number distributions depart from standard models, illustrating the value of these single-molecule observations in constraining the mechanism of cooperativity. While a complete alternative microscopic model cannot be defined at present, the addition of subunit-occupancy-dependent cooperativity in hydrolysis yields distributions consistent with the data. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
18. Toxic tips: Ethylene glycol
- Author
-
Luttrell, William E. and Conley, Nicholas L.
- Published
- 2012
- Full Text
- View/download PDF
19. DCDHF Fluorophores for Single-Molecule Imaging in Cells.
- Author
-
Lord, Samuel J., Conley, Nicholas R., Lee, Hsiao-lu D., Nishimura, Stefanie Y., Pomerantz, Andrea K., Willets, Katherine A., Lu, Zhikuan, Wang, Hui, Liu, Na, Samuel, Reichel, Weber, Ryan, Semyonov, Alexander, He, Meng, Twieg, Robert J., and Moerner, W. E.
- Published
- 2009
- Full Text
- View/download PDF
20. Benzene
- Author
-
Luttrell, William E. and Conley, Nicholas L.
- Published
- 2011
- Full Text
- View/download PDF
21. 1158-P: Genetic Dissection of a Vagal Neurocircuit for Blood Glucose Regulation.
- Author
-
CONLEY, NICHOLAS J., LI, CHELSEA, and CAMPBELL, JOHN
- Abstract
Neurons of the hindbrain's dorsal motor nucleus of the vagus (DMV) in the hindbrain control key physiological functions related to diabetes, including pancreatic hormone secretion and food passage through the GI tract. Different subtypes of DMV neurons, or "functional units," are thought to mediate distinct physiological roles. However, a lack of definition and access to these subtypes has greatly limited what is known about them. Thus, there is much to learn about the nature of the DMV neurons controlling insulin release and gastric motility, how they function, and how they can be targeted to treat diabetes. To gain traction on this issue, we began by classifying DMV neuron subtypes based on their gene expression, using high-throughput single-nuclei RNA-seq in a mouse model. Our analysis revealed seven, molecularly-distinct subtypes of DMV neurons, two of which were respectively marked by their expression of the genes Calb2 and Grp. Fluorescence in situ hybridization revealed that Calb2 DMV neurons and Grp DMV neurons occupy different subregions of the DMV, suggesting they may innervate different parts of the digestive system. To investigate this, we stained the axons of Calb2 DMV neurons and Grp DMV neurons and imaged them in optically cleared stomach and pancreas from mouse. These studies revealed that Calb2 DMV neurons innervate pancreas but not stomach, whereas Grp DMV neurons innervate neither organ. To then determine whether Calb2 DMV neurons control pancreas endocrine function, we used intersectional optogenetics to stimulate Calb2 DMV neurons while assessing blood glucose levels in vivo. Preliminary data indicate that activating Calb2 DMV neurons causes a rapid and substantial decrease in blood glucose levels. Together our results not only identify Calb2 DMV neurons as pancreas afferents that can lower blood glucose, but reveal a "labeled line" logic to the organization of vagal motor neurons, in which genetically-distinct neuron subtypes innervate different digestive organs to control their function. Disclosure: N. J. Conley: None. C. Li: None. J. Campbell: None. Funding: American Diabetes Association/Pathway to Stop Diabetes (1-18-INI-14 to J.C.) [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. High School Students as Citizen Scientists to Decrease Radon Exposure.
- Author
-
Hahn, Ellen J., Wilmhoff, Craig, Rayens, Mary Kay, Conley, Nicholas B., Morris, Emily, Larck, Angela, Allen, Trista, and Pinney, Susan M.
- Published
- 2020
- Full Text
- View/download PDF
23. The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits.
- Author
-
Li, Monica M., Madara, Joseph C., Steger, Jennifer S., Krashes, Michael J., Balthasar, Nina, Campbell, John N., Resch, Jon M., Conley, Nicholas J., Garfield, Alastair S., and Lowell, Bradford B.
- Subjects
- *
HYPOTHALAMUS , *PREVENTION of obesity , *INGESTION , *OBESITY , *FOOD supply - Abstract
SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVHSIM1 population, melanocortin-4 receptor-expressing (PVHMC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVHSIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVHPDYN) neurons, which notably lack MC4Rs, function independently and additively with PVHMC4R neurons to account for the totality of PVHSIM1 neuron-mediated satiety. Moreover, PVHPDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVHMC4R neurons. While PVHPDYN and PVHMC4R neurons both project to the parabrachial complex (PB), they synaptically engage distinct efferent nodes, the pre-locus coeruleus (pLC), and central lateral parabrachial nucleus (cLPBN), respectively. PB-projecting PVHPDYN neurons, like PVHMC4R neurons, receive input from interoceptive ARCAgRP neurons, respond to caloric state, and are sufficient and necessary to control food intake. This expands the CNS satiety circuitry to include two non-overlapping PVH to hindbrain circuits. • PVH neurons cause satiety, of which ∼50% is accounted for by PVHMC4R neurons • PVHPDYN neurons are identified as novel satiety neurons that prevent obesity • PVHPDYN and PVHMC4R neurons are distinct and equipotent, producing additive effects • PVHPDYN and PVHMC4R neurons use separate efferent circuits to regulate appetite Li et al. discover that PVHPDYN neurons, additively with PVHMC4R neurons, are responsible for PVH-mediated satiety. Both PVH neurons are distinct, are equipotent, and use parallel projections to different aspects of the parabrachial complex to cause satiety and prevent obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
24. Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.
- Author
-
Kim P, Sanchez AM, Penke TJR, Tuson HH, Kime JC, McKee RW, Slone WL, Conley NR, McMillan LJ, Prybol CJ, and Garofolo PM
- Abstract
Background: The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study., Methods: This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 10
12 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing., Findings: Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10., Interpretation: A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE., Funding: Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA)., Competing Interests: Declaration of interests All authors are currently or were previously employees of Locus Biosciences and owned stock or stock options in the company. WLS is currently employed at Viridian and no longer owns stock in Locus Biosciences., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)- Published
- 2024
- Full Text
- View/download PDF
25. Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior.
- Author
-
Strain MM, Conley NJ, Kauffman LS, Espinoza L, Fedorchak S, Martinez PC, Crook ME, Jalil M, Hodes GE, Abbott SBG, Güler AD, Campbell JN, and Boychuk CR
- Abstract
Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVN
NA ) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV ) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA . Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis., Competing Interests: DECLARATION OF INTEREST Authors declare no competing interest.- Published
- 2023
- Full Text
- View/download PDF
26. The Property-Based Practical Applications and Solutions of Genetically Encoded Acetylcholine and Monoamine Sensors.
- Author
-
Chen J, Cho KE, Skwarzynska D, Clancy S, Conley NJ, Clinton SM, Li X, Lin L, and Zhu JJ
- Subjects
- Animals, Humans, Acetylcholine physiology, Biogenic Monoamines physiology, Cell Communication genetics, Neurons physiology, Neurotransmitter Agents physiology, Synapses physiology, Synaptic Transmission physiology
- Abstract
Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. In vitro and in vivo experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter sensors in expanding our knowledge of various behaviors and diseases, including Alzheimer's disease, sleeping disorders, tumorigenesis, and many others., (Copyright © 2021 the authors.)
- Published
- 2021
- Full Text
- View/download PDF
27. A selenium analogue of firefly D-luciferin with red-shifted bioluminescence emission.
- Author
-
Conley NR, Dragulescu-Andrasi A, Rao J, and Moerner WE
- Subjects
- Animals, Cell Line, Tumor, Fireflies enzymology, Firefly Luciferin chemical synthesis, Humans, Luciferases, Firefly metabolism, Luminescent Measurements, Magnetic Resonance Imaging, Mice, Mice, Nude, Neoplasms diagnostic imaging, Radionuclide Imaging, Substrate Specificity, Transplantation, Heterologous, Firefly Luciferin chemistry, Selenium chemistry
- Abstract
A selenium analogue of amino-D-luciferin, aminoseleno-D-luciferin, is synthesized and shown to be a competent substrate for the firefly luciferase enzyme. It has a red-shifted bioluminescence emission maximum at 600 nm and is suitable for bioluminescence imaging studies in living subjects., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
- View/download PDF
28. Molecules and methods for super-resolution imaging.
- Author
-
Thompson MA, Biteen JS, Lord SJ, Conley NR, and Moerner WE
- Subjects
- Animals, Azides chemistry, Bacteria ultrastructure, Humans, Imaging, Three-Dimensional, Molecular Structure, Photochemistry, Fluorescent Dyes chemistry, Microscopy, Fluorescence methods, Photons
- Abstract
By looking at a fluorescently labeled structure one molecule at a time, it is possible to side-step the optical diffraction limit and obtain "super-resolution" images of small nanostructures. In the Moerner Lab, we seek to develop both molecules and methods to extend super-resolution fluorescence imaging. Methodologies and protocols for designing and characterizing fluorophores with switchable fluorescence required for super-resolution imaging are reported. These fluorophores include azido-DCDHF molecules, covalently linked Cy3-Cy5 dimers, and also the first example of a photoswitchable fluorescent protein, enhanced yellow fluorescent protein (EYFP). The imaging of protein superstructures in living Caulobacter crescentus bacteria is used as an example of the power of super-resolution imaging by single-molecule photoswitching to extract information beyond the diffraction limit. Finally, a new method is described for obtaining three-dimensional super-resolution information using a double-helix point-spread function., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
29. Toward nanometer-scale optical photolithography: utilizing the near-field of bowtie optical nanoantennas.
- Author
-
Sundaramurthy A, Schuck PJ, Conley NR, Fromm DP, Kino GS, and Moerner WE
- Subjects
- Color, Microscopy, Atomic Force, Nanostructures ultrastructure, Optics and Photonics, Nanostructures chemistry, Nanotechnology instrumentation, Nanotechnology methods
- Abstract
Optically resonant metallic bowtie nanoantennas are utilized as fabrication tools for the first time, resulting in the production of polymer resist nanostructures <30 nm in diameter at record low incident multiphoton energy densities. The nanofabrication is accomplished via nonlinear photopolymerization, which is initiated by the enhanced, confined optical fields surrounding the nanoantenna. The position, size, and shape of the resist nanostructures directly correlate with rigorous finite-difference time-domain computations of the field distribution, providing a nanometer-scale measurement of the actual field confinement offered by single optical nanoantennas. In addition, the size of the photoresist regions yields strong upper bounds on photoacid diffusion and resist resolution in SU-8, demonstrating a technique that can be generalized to the study of many current and yet-to-be-developed photoresist systems.
- Published
- 2006
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.