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1.
CA Cancer J Clin ; 71(1): 78-92, 2021 01.
Article in English | MEDLINE | ID: mdl-33002206

ABSTRACT

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.


Subject(s)
Geriatrics/statistics & numerical data , Medical Oncology/statistics & numerical data , Neoplasms/therapy , Patient Participation/psychology , Patient Selection , Aged , Aged, 80 and over , Clinical Trials as Topic , Geriatrics/methods , Geriatrics/trends , Humans , Medical Oncology/methods , Medical Oncology/trends , Neoplasms/diagnosis , Patient Participation/statistics & numerical data , United States
2.
Hippocampus ; 33(11): 1208-1227, 2023 11.
Article in English | MEDLINE | ID: mdl-37705290

ABSTRACT

Calcium (Ca2+ ) imaging reveals a variety of correlated firing in cultures of dissociated hippocampal neurons, pinpointing the non-synaptic paracrine release of glutamate as a possible mediator for such firing patterns, although the biophysical underpinnings remain unknown. An intriguing possibility is that extracellular glutamate could bind metabotropic receptors linked with inositol trisphosphate (IP3 ) mediated release of Ca2+ from the endoplasmic reticulum of individual neurons, thereby modulating neural activity in combination with sarco/endoplasmic reticulum Ca2+ transport ATPase (SERCA) and voltage-gated Ca2+ channels (VGCC). However, the possibility that such release may occur in different neuronal compartments and can be inherently stochastic poses challenges in the characterization of such interplay between various Ca2+ channels. Here we deploy biophysical modeling in association with Monte Carlo parameter sampling to characterize such interplay and successfully predict experimentally observed Ca2+ patterns. The results show that the neurotransmitter level at the plasma membrane is the extrinsic source of heterogeneity in somatic Ca2+ transients. Our analysis, in particular, identifies the origin of such heterogeneity to an intrinsic differentiation of hippocampal neurons in terms of multiple cellular properties pertaining to intracellular Ca2+ signaling, such as VGCC, IP3 receptor, and SERCA expression. In the future, the biophysical model and parameter estimation approach used in this study can be upgraded to predict the response of a system of interconnected neurons.


Subject(s)
Hippocampus , Neurons , Hippocampus/physiology , Neurons/physiology , Calcium/metabolism , Endoplasmic Reticulum/metabolism , Glutamic Acid/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Calcium Signaling/physiology
3.
Ophthalmic Plast Reconstr Surg ; 36(5): 490-496, 2020.
Article in English | MEDLINE | ID: mdl-32134771

ABSTRACT

PURPOSE: To determine the association of Fitzpatrick skin type (FST) with conjunctival melanoma. METHODS: Retrospective case series of 540 patients with conjunctival melanoma to assess clinical features and outcomes per FST. RESULTS: The FST was Type I (n = 126, 23%), II (n = 337, 62%), III (n = 56, 10%), IV (n = 8, 2%), V (n = 12, 2%), and VI (n = 1, <1%). A comparison (FST I vs. II vs. III, IV, V, and VI) revealed Types I and II associated with older mean patient age (63.9 vs. 60.7 vs. 51.1 years, p < 0.001), greater percentage of female patients (68% vs. 44% vs. 42%, p < 0.001), lower frequency of complexion associated melanosis (1% vs. 2% vs. 13%, p < 0.001), smaller tumor thickness (2.1 vs. 2.8 vs. 3.6 mm, p = 0.01), and less eyelid involvement (13% vs. 13% vs. 28%, p = 0.02). Kaplan-Meier estimates for 5-year risk showed no difference by Types for visual acuity loss ≥3 lines, local tumor recurrence, exenteration, metastasis, or death. CONCLUSION AND RELEVANCE: Most patients with conjunctival melanoma show FST I or II, and this demonstrated no association with 5-year rate of vision loss, tumor recurrence, exenteration, metastasis, or death.


Subject(s)
Conjunctival Neoplasms , Melanoma , Melanosis , Conjunctival Neoplasms/epidemiology , Conjunctival Neoplasms/therapy , Female , Humans , Melanoma/diagnosis , Melanoma/epidemiology , Melanoma/therapy , Neoplasm Recurrence, Local , Retrospective Studies
4.
Child Youth Serv Rev ; 1192020 Dec.
Article in English | MEDLINE | ID: mdl-33041412

ABSTRACT

Limited rigorous research has been conducted to evaluate the impact of interventions designed to promote the successful transitions of young people exiting foster care. The current study builds on previous experimental evaluations of the My Life Model (MLM) for self-determination enhancement, which demonstrated effectiveness in improving educational and transition-to-adulthood outcomes for youth in foster care with disabilities, including those with mental health challenges. The model features one-on-one youth-directed coaching and near-peer mentoring to increase self-determination and goal achievement. The current study was the first to test the impact of the model with a diverse population-based cohort of youth aged 16.5-18.5 in foster care (N=293), including those with and without disabilities, on key model outcome indicators of self-determination and self-efficacy. This study also explored potential moderation by disability status, trauma symptoms, placement stability, and placement restrictiveness. Findings show that, compared to the randomized control group, the treatment group had greater post-intervention and one-year follow-up gains on several indicators of self-determination. Moderation analysis demonstrated no difference in intervention effectiveness for youth with or without disabilities, suggesting the universality of this approach. Findings also suggest that foster youth participants with low-to-average risks in terms of placement stability, placement restrictiveness, and traumatic stress levels seem to benefit most from the intervention, although youth who are at higher risk due to low placement stability, high placement restriction, and high traumatic stress still showed some benefit of participating in the intervention on some measures. My Life is one of only a few intervention models with experimental evidence of effectiveness with older youth in foster care. This validation study establishes that the approach has benefits for both youth with and without disabilities, as well as providing the first information available on the influence of critical barriers facing many youth in care.

5.
Ann Surg ; 270(2): 302-308, 2019 08.
Article in English | MEDLINE | ID: mdl-29697454

ABSTRACT

OBJECTIVE: To report 1-year results from a 5-year mandated study. SUMMARY BACKGROUND DATA: In 2012, the United States Food and Drug Administration approved magnetic sphincter augmentation (MSA) with the LINX Reflux Management System (Torax Medical, Shoreview, MN), a novel device for the surgical treatment of gastroesophageal reflux disease (GERD). Continued assessment of safety and effectiveness has been monitored in a Post Approval Study. METHODS: Multicenter, prospective study of patients with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastricduodenoscopy and esophageal pH monitoring, and use of proton pump inhibitors. RESULTS: A total of 200 patients (102 males, 98 females) with a mean age of 48.5 years (range 19.7-71.6) were treated with MSA between March 2013 and August 2015. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of patients had normal esophageal acid exposure time (% time pH<4 ≤5.3%). GERD Health-Related Quality of Life scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of patients meeting the predefined success criteria of at least a 50% reduction in total GERD Health-Related Quality of Life score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious adverse events were reported. CONCLUSIONS: Safety and effectiveness of magnetic sphincter augmentation has been demonstrated outside of an investigational setting to further confirm MSA as treatment for GERD.


Subject(s)
Deglutition/physiology , Esophageal Sphincter, Lower/surgery , Gastroesophageal Reflux/surgery , Magnets , Adult , Aged , Esophageal Sphincter, Lower/physiopathology , Esophageal pH Monitoring , Female , Follow-Up Studies , Gastroesophageal Reflux/metabolism , Gastroesophageal Reflux/physiopathology , Humans , Male , Middle Aged , Prospective Studies , Prosthesis Design , Surveys and Questionnaires , Time Factors , Treatment Outcome , Young Adult
6.
Ann Emerg Med ; 74(1): 140-152, 2019 07.
Article in English | MEDLINE | ID: mdl-30470513

ABSTRACT

STUDY OBJECTIVE: Rapid growth in emergency department (ED) triage literature has been accompanied by diversity in study design, methodology, and outcome assessment. We aim to synthesize existing ED triage literature by using a framework that enables performance comparisons and benchmarking across triage systems, with respect to clinical outcomes and reliability. METHODS: PubMed, EMBASE, Scopus, and Web of Science were systematically searched for studies of adult ED triage systems through 2016. Studies evaluating triage systems with evidence of widespread adoption (Australian Triage Scale, Canadian Triage and Acuity Scale, Emergency Severity Index, Manchester Triage Scale, and South African Triage Scale) were cataloged and compared for performance in identifying patients at risk for mortality, critical illness and hospitalization, and interrater reliability. This study was performed and reported in adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A total of 6,160 publications were identified, with 182 meeting eligibility criteria and 50 with sufficient data for inclusion in comparative analysis. The Canadian Triage and Acuity Scale (32 studies), Emergency Severity Index (43), and Manchester Triage Scale (38) were the most frequently studied triage scales, and all demonstrated similar performance. Most studies (6 of 8) reported high sensitivity (>90%) of triage scales for identifying patients with ED mortality as high acuity at triage. However, sensitivity was low (<80%) for identification of patients who had critical illness outcomes and those who died within days of the ED visit or during the index hospitalization. Sensitivity varied by critical illness and was lower for severe sepsis (36% to 74%), pulmonary embolism (54%), and non-ST-segment elevation myocardial infarction (44% to 85%) compared with ST-segment elevation myocardial infarction (56% to 92%) and general outcomes of ICU admission (58% to 100%) and lifesaving intervention (77% to 98%). Some proportion of hospitalized patients (3% to 45%) were triaged to low acuity (level 4 to 5) in all studies. Reliability measures (κ) were variable across evaluations, with only a minority (11 of 42) reporting κ above 0.8. CONCLUSION: We found that a substantial proportion of ED patients who die postencounter or are critically ill are not designated as high acuity at triage. Opportunity to improve interrater reliability and triage performance in identifying patients at risk of adverse outcome exists.


Subject(s)
Emergency Medicine/standards , Emergency Service, Hospital/standards , Triage/methods , Aged , Aged, 80 and over , Australia/epidemiology , Benchmarking/methods , Canada/epidemiology , Critical Illness/epidemiology , Critical Illness/mortality , Emergency Medicine/statistics & numerical data , Emergency Service, Hospital/statistics & numerical data , Hospitalization , Humans , Myocardial Infarction/epidemiology , Myocardial Infarction/mortality , Myocardial Infarction/physiopathology , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Pulmonary Embolism/mortality , Reproducibility of Results , Sepsis/epidemiology , Sepsis/mortality , Severity of Illness Index , South Africa/epidemiology , Task Performance and Analysis
7.
Metab Eng ; 47: 60-72, 2018 05.
Article in English | MEDLINE | ID: mdl-29530749

ABSTRACT

Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway "breakage", using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism. Next, using multi-omics data, we demonstrate that endogenous E. coli metabolism is globally impacted by IPP accumulation, which slows nutrient uptake, decreases ATP levels, and perturbs nucleotide metabolism. We also observe the extracellular accumulation of IPP and present preliminary evidence that IPP can be transported by E. coli, findings that might be broadly relevant for the study of isoprenoid biosynthesis. Finally, we discover that IPP accumulation leads to the formation of ApppI, a nucleotide analog of IPP that may contribute to observed toxicity phenotypes. This comprehensive assessment of IPP stress suggests potential strategies for the alleviation of prenyl diphosphate toxicity and highlights possible engineering targets for improved IPP flux and high titer isoprenoid production.


Subject(s)
Escherichia coli/genetics , Escherichia coli/metabolism , Hemiterpenes/biosynthesis , Models, Biological , Terpenes/metabolism , Organophosphorus Compounds
8.
Metab Eng ; 34: 25-35, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26708516

ABSTRACT

Branched C5 alcohols are promising biofuels with favorable combustion properties. A mevalonate (MVA)-based isoprenoid biosynthetic pathway for C5 alcohols was constructed in Escherichia coli using genes from several organisms, and the pathway was optimized to achieve over 50% theoretical yield. Although the MVA pathway is energetically less efficient than the native methylerythritol 4-phosphate (MEP) pathway, implementing the MVA pathway in bacterial hosts such as E. coli is advantageous due to its lack of endogenous regulation. The MVA and MEP pathways intersect at isopentenyl diphosphate (IPP), the direct precursor to isoprenoid-derived C5 alcohols and initial precursor to longer chain terpenes, which makes independent regulation of the pathways difficult. In pursuit of the complete "decoupling" of the MVA pathway from native cellular regulation, we designed novel IPP-bypass MVA pathways for C5 alcohol production by utilizing promiscuous activities of two enzymes, phosphomevalonate decarboxylase (PMD) and an E. coli-endogenous phosphatase (AphA). These bypass pathways have reduced energetic requirements, are further decoupled from intrinsic regulation, and are free from IPP-related toxicity. In addition to these benefits, we demonstrate that reduced aeration rate has less impact on the bypass pathway than the original MVA pathway. Finally, we showed that performance of the bypass pathway was primarily determined by the activity of PMD. We designed PMD mutants with improved activity and demonstrated titer increases in the mutant strains. These modified pathways would be a good platform for industrial production of isopentenol and related chemicals such as isoprene.


Subject(s)
Escherichia coli/metabolism , Hemiterpenes/metabolism , Metabolic Engineering/methods , Metabolic Networks and Pathways/physiology , Mevalonic Acid/metabolism , Organophosphorus Compounds/metabolism , Pentanols/metabolism , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Metabolic Flux Analysis , Metabolome/physiology , Pentanols/isolation & purification , Signal Transduction/physiology
9.
Biotechnol Bioeng ; 111(8): 1648-58, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24615242

ABSTRACT

The ability to rapidly assess and optimize heterologous pathway function is critical for effective metabolic engineering. Here, we develop a systematic approach to pathway analysis based on correlations between targeted proteins and metabolites and apply it to the microbial production of isopentenol, a promising biofuel. Starting with a seven-gene pathway, we performed a correlation analysis to reduce pathway complexity and identified two pathway proteins as the primary determinants of efficient isopentenol production. Aided by the targeted quantification of relevant pathway intermediates, we constructed and subsequently validated a conceptual model of isopentenol pathway function. Informed by our analysis, we assembled a strain which produced isopentenol at a titer 1.5 g/L, or 46% of theoretical yield. Our engineering approach allowed us to accurately identify bottlenecks and determine appropriate pathway balance. Paired with high-throughput cloning techniques and analytics, this strategy should prove useful for the analysis and optimization of increasingly complex heterologous pathways.


Subject(s)
Biofuels/microbiology , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Industrial Microbiology/methods , Metabolic Engineering/methods , Pentanols/metabolism , Acetates/metabolism , Biosynthetic Pathways , Escherichia coli/genetics , Escherichia coli/growth & development , Escherichia coli Proteins/genetics , Glucose/metabolism , Models, Biological , Proteomics/methods
10.
RSC Adv ; 14(9): 6339-6359, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38380237

ABSTRACT

This review provides a comprehensive overview of the significance of aurone cores in organic chemistry, highlighting their crucial role as synthetic intermediates. With their innate electrophilic reactivity and convenient accessibility, aurone cores play a vital role in catalysing the development of novel methodologies and facilitating the creation of intricate compounds. The objective of this review is to present a current and insightful compilation that summarizes the progress in aurone synthetic transformations, focusing on diverse cycloaddition ([3 + 2], [4 + 2], [4 + 3], [10 + 2]) and annulation reactions.

11.
Int Urol Nephrol ; 55(5): 1109-1116, 2023 May.
Article in English | MEDLINE | ID: mdl-36913168

ABSTRACT

PURPOSE: Pain management is central in the treatment of urolithiasis. We aimed to estimate the impact of the 2017 Department of Health and Human Services declaration of an opioid crisis on prescribing patterns of opioids and NSAIDs in emergency department visits for urolithiasis. METHODS: The National Health Ambulatory Medical Care Survey (NHAMCS) was queried for emergency department visits of adults with a diagnosis of urolithiasis. The association between urolithiasis and narcotic and NSAIDs prescription patterns was evaluated and compared at pre-declaration (2014-2016) to post-declaration (2017-2018) periods. RESULTS: Opioids were prescribed in about 211 million (41.1%) out of 513 million emergency department visits, over a 5-year period. Diagnosis of urolithiasis accounted for 1.9% of the visits (6.0 million). The use of opioids was higher in urolithiasis (82.7%) compared to non-urolithiasis diagnosis (40.3%), as well as the use of multiple opioids per visit (p < 0.01 for all). There was an overall decrease in opioid prescriptions in the post-declaration period, - 4.3% for urolithiasis (p = 0.254) and - 5.6% for non-urolithiasis visits (p < 0.05). A decrease in the use of hydromorphone (- 47.5%. p < 0.001), an increase in the use of morphine (+ 59.7% p = 0.006), and an increase of 'other' opioids (+ 98.8%, p < 0.041), were observed. Opioids combined with NSAIDs comprised 72.6% of the opioid prescriptions and 62.3% of all analgesic prescriptions in visits with urolithiasis diagnosis. CONCLUSIONS: The use of opioids when managing urolithiasis decreased 4.3% after the crisis declaration; however, statistically are not different from pre-declaration numbers. Most often, opioids were prescribed with NSAIDs in urolithiasis patients.


Subject(s)
Analgesics, Opioid , Analgesics , Adult , Humans , Analgesics, Opioid/therapeutic use , Emergency Service, Hospital , Prescriptions , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Practice Patterns, Physicians'
12.
Microbiology (Reading) ; 158(Pt 11): 2781-2788, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22902727

ABSTRACT

Pseudomonas putida F1 is unable to grow on styrene due to the accumulation of 3-vinylcatechol, a toxic metabolite that is produced through the toluene degradation (tod) pathway and causes catechol-2,3-dioxygenase (C23O) inactivation. In this study, we characterized a spontaneous F1 mutant, designated SF1, which acquired the ability to grow on styrene and did not accumulate 3-vinylcatechol. Whereas adaptation to new aromatic substrates has typically been shown to involve increased C23O activity or the acquisition of resistance to C23O inactivation, SF1 retained wild-type C23O activity. Surprisingly, SF1 grew more slowly on toluene, its native substrate, and exhibited reduced toluene dioxygenase (TDO) activity (approximately 50 % of that of F1), the enzyme responsible for ring hydroxylation and subsequent production of 3-vinylcatechol. DNA sequence analysis of the tod operon of SF1 revealed a single base pair mutation in todA (C479T), a gene encoding the reductase component of TDO. Replacement of the wild-type todA allele in F1 with todA(C479T) reduced TDO activity to SF1 levels, obviated vinylcatechol accumulation, and conferred the ability to grow on styrene. This novel 'less is more' strategy - reduced catechol production as a means to expand growth substrate range - sheds light on an alternative approach for managing catechol toxicity during the metabolism of aromatic compounds.


Subject(s)
Catechols/metabolism , Pseudomonas putida/growth & development , Pseudomonas putida/metabolism , Styrene/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Catechol 2,3-Dioxygenase/genetics , Catechol 2,3-Dioxygenase/metabolism , Mutation , Oxygenases/genetics , Oxygenases/metabolism , Pseudomonas putida/enzymology , Pseudomonas putida/genetics , Toluene/metabolism
13.
Rapid Commun Mass Spectrom ; 26(6): 611-5, 2012 Mar 30.
Article in English | MEDLINE | ID: mdl-22328213

ABSTRACT

RATIONALE: The nanostructure-initiator mass spectrometry based enzyme assay (Nimzyme) provides a rapid method for screening glycan modifying reactions. However, this approach cannot resolve stereospecific reactions which are common in glycobiology and are typically assayed using lower-throughput methods (gas chromatography/mass spectrometry (GC/MS) or liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis) often in conjunction with stable isotopically labeled reactants. However, in many applications, library size necessitates the development of higher-throughput screening approaches of stereospecific reactions from crude sample preparations. Therefore, here we test the approach of utilizing Nimzyme linkers with unique masses to encode substrate identity such that this assay can resolve stereospecific reactions. METHODS: We utilize the nanostructure-initiator mass spectrometry (NIMS) enzyme assay in conjuction with an accurate mass tagging approach where each reactant is tagged with a unique perfluoronated tail. Mass spectrometric analysis was conducted using conventional MALDI-TOF instrumentation. RESULTS: Stereospecific reaction pathways of three stereoisomers (maltose, lactose and cellobiose) to afford the same product glucose were resolved simutaneously due to the presence of unique fluorous tags on both reactants and products. Not only purified enzymes, but also crude cell lysates can be used in this assay. CONCLUSIONS: The Nimzyme assay with accurate mass tagging provides a rapid method for screening for targeted stereospecific reactions using mass spectrometry and may be useful for high-throughput screening and functional annotation of a wide range of glycan-modifying enzymes.


Subject(s)
Cellobiose/metabolism , Enzyme Assays/methods , Lactose/metabolism , Maltose/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Escherichia coli/enzymology , Glucose/metabolism , Nanostructures/chemistry , Stereoisomerism , Substrate Specificity
15.
RSC Adv ; 12(42): 27246-27252, 2022 Sep 22.
Article in English | MEDLINE | ID: mdl-36276024

ABSTRACT

A rapid and efficient method has been developed for the synthesis of 13,14-dimethyl-6,7-dihydrodibenzo[b,j][4,7]phenanthroline derivatives (3a-d) through the Friedländer condensation of 2-aminoarylketone with 1,4-cyclohexanedione under solvent-free conditions using p-toluenesulphonic acid. The synthetic utility of compounds 3a, 3b, and 3c was demonstrated by synthesizing compounds 6a-kvia Suzuki coupling, 8 by Buchwald-Hartwig amination, and 9a-bvia NBS bromination. Significantly, the emission band corresponding to the π-π* electronic transition of compounds 3a, 6a, 6d, 6f, and 8 showed a redshift with increasing polarity of the solvents. Molar extinction coefficient (ε), Stoke's shift (Δ[italic small upsilon, Greek, macron]), and quantum yield (Φ f) were calculated for all these compounds.

16.
ACS Omega ; 7(24): 20605-20618, 2022 Jun 21.
Article in English | MEDLINE | ID: mdl-35755376

ABSTRACT

A facile and efficient method has been developed for the synthesis of quinoline-fused fluorescent dihydro/spiro-quinazolinones. A plausible mechanism involving an acid-mediated enaminone intermediate is provided. The reaction proceeded using p-toluene sulfonic acid as a green promoter. The methodology was successful in synthesizing various quinoline-appended spiro-quinazolinones 4a-o. The synthetic utility of compounds 4a-o was demonstrated by synthesizing compounds 6a-d via Suzuki coupling as a key reaction. Significantly, the π-π* electronic transition of compounds 4c and 4k showed a blue shift. The molar extinction coefficient (ε), Stoke's shift (Δu̅), and quantum yield (Φf)c were calculated for these derivatives (4c and 4k).

17.
Global Spine J ; 12(8): 1731-1735, 2022 Oct.
Article in English | MEDLINE | ID: mdl-33504205

ABSTRACT

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: The purpose of the study is to evaluate the role of supine radiographs in determining flexibility of thoracic and thoracolumbar curves. METHODS: Ninety operative AIS patients with 2-year follow-up from a single institution were queried and classified into MT structural and TL structural groups. Equations were derived using linear regression to compute cut-off values for MT and TL curves. Thresholds were externally validated in a separate database of 60 AIS patients, and positive and negative predictive values were determined for each curve. RESULTS: MT supine values were highly predictive of MT side-bending values (TL group: 0.63, P < 0.001; MT group: 0.66, P = 0.006). Similarly, TL supine values were highly predictive of TL side-bending values (TL group: 0.56, P = 0.001 MT group: 0.68, P = 0.001). From our derived equations, MT and TL curves were considered structural on supine films if they were ≥ 30° and 35°, respectively. Contingency table analysis of external validity sample showed that supine films were highly predictive of structurality of MT curve (Sensitivity = 0.91, PPV = 0.95, NPV = 0.81) and TL curve (Sensitivity = 0.77, PPV = 0.81, NPV = 0.94). ROC analysis revealed that the area under curve for MT structurality from supine films was 0.931 (SEM: 0.03, CI: 0.86-0.99, P < 0.001) and TL structurality from supine films was 0.922 (SEM: 0.03, CI- 0.84-0.98, P < 0.001). CONCLUSIONS: A single preoperative supine radiograph is highly predictive of side-bending radiographs to assess curve flexibility in AIS. A cut-off of ≥ 30° for MT and ≥ 35° for TL curves in supine radiographs can determine curve structurality.

18.
Microbiology (Reading) ; 157(Pt 1): 89-98, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20929952

ABSTRACT

Pseudomonas putida F1 cannot grow on styrene despite being able to degrade it through the toluene degradation (tod) pathway. Previous work had suggested that this was because TodF, the meta-fission product (MFP) hydrolase, was unable to metabolize the styrene MFP 2-hydroxy-6-vinylhexa-2,4-dienoate. Here we demonstrate via kinetic and growth analyses that the substrate specificity of TodF is not the limiting factor preventing F1 from growing on styrene. Rather, we found that the metabolite 3-vinylcatechol accumulated during styrene metabolism and that micromolar concentrations of this intermediate inactivated TodE, the catechol-2,3-dioxygenase (C23O) responsible for its cleavage. Analysis of cells growing on styrene suggested that inactivation of TodE and the subsequent accumulation of 3-vinylcatechol resulted in toxicity and cell death. We found that simply overexpressing TodE on a plasmid (pTodE) was all that was necessary to allow F1 to grow on styrene. Similar results were also obtained by expressing a related C23O, DmpB from Pseudomonas sp. CF600, in tandem with its plant-like ferredoxin, DmpQ (pDmpQB). Further analysis revealed that the ability of F1 (pDmpQB) and F1 (pTodE) to grow on styrene correlated with increased C23O activity as well as resistance of the enzyme to 3-vinylcatechol-mediated inactivation. Although TodE inactivation by 3-halocatechols has been studied before, to our knowledge, this is the first published report demonstrating inactivation by a 3-vinylcatechol. Given the ubiquity of catechol intermediates in aromatic hydrocarbon metabolism, our results further demonstrate the importance of C23O inactivation as a determinant of growth substrate specificity.


Subject(s)
Bacterial Proteins/metabolism , Catechol 2,3-Dioxygenase/metabolism , Gene Expression , Pseudomonas putida/metabolism , Styrene/metabolism , Bacterial Proteins/genetics , Catechol 2,3-Dioxygenase/genetics , Catechols/metabolism , Catechols/toxicity , Hydrolases/metabolism , Plasmids , Pseudomonas putida/growth & development , Substrate Specificity , Vinyl Compounds/metabolism , Vinyl Compounds/toxicity
19.
Adv Appl Microbiol ; 74: 1-33, 2011.
Article in English | MEDLINE | ID: mdl-21459192

ABSTRACT

Although the biodegradation of aromatic compounds has been studied for over 40 years, there is still much to learn about the strategies bacteria employ for growth on novel substrates. Elucidation of these strategies is crucial for predicting the environmental fate of aromatic pollutants and will provide a framework for the development of engineered bacteria and degradation pathways. In this chapter, we provide an overview of studies that have advanced our knowledge of bacterial adaptation to aromatic compounds. We have divided these strategies into three broad categories: (1) recruitment of catabolic genes, (2) expression of "repair" or detoxification proteins, and (3) direct alteration of enzymatic properties. Specific examples from the literature are discussed, with an eye toward the molecular mechanisms that underlie each strategy.


Subject(s)
Bacteria , Biodegradation, Environmental , Bacteria/genetics , Bacterial Proteins/genetics , Metabolic Networks and Pathways , Organic Chemicals/metabolism
20.
Dev Neurorehabil ; 24(1): 8-17, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32372674

ABSTRACT

Background: Rehabilitation in cerebral palsy (CP) seeks to harness neuroplasticity to improve movement, including walking, yet cortical activation underlying gait is not well understood. Methods: We used electroencephalography (EEG) to compare motor related cortical activity, measured by mu rhythm, during quiet standing and treadmill walking in 10 children with unilateral CP and 10 age- and sex-matched children with typical development (TD). Peak mu band frequency, mu rhythm desynchronization (MRD), and gait related intra- and inter-hemispheric coherence were examined. Results: MRD during walking was observed bilaterally over motor cortex in both cohorts but peak mu band frequency showing MRD was significantly lower in CP compared to TD. Coherence during quiet standing between motor and frontal regions was significantly higher in the non-dominant compared to dominant hemisphere in CP with no hemispheric differences in TD. Conclusions: EEG-based measures should be further investigated as clinical biomarkers for atypical motor development and to assess rehabilitation effectiveness.


Subject(s)
Brain Waves , Cerebral Palsy/physiopathology , Gait , Child , Female , Humans , Male , Standing Position
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