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1.
Biomolecules ; 13(6)2023 06 02.
Article in English | MEDLINE | ID: mdl-37371516

ABSTRACT

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.


Subject(s)
Morphine , Spiro Compounds , Mice , Animals , Morphine/pharmacology , Analgesics, Opioid/pharmacology , Fentanyl/pharmacology
2.
Article in English | MEDLINE | ID: mdl-36498181

ABSTRACT

This review identifies the most promising intervention strategies for promoting the purchase and consumption of healthier items within U.S. grocery retail settings, with a particular focus on those strategies that may be most effective when implemented within SNAP-authorized retail settings. Searches of nine electronic databases, as well as forward and backward searches, yielded 1942 studies. After being screened, 73 peer-reviewed academic articles were identified for inclusion. Of these, 33 analyzed single-component interventions, while 40 assessed multi-component interventions. The following unique intervention types were considered as evaluated in these studies for their ability to increase healthy item purchasing and consumption: (1) nutrition scoring, (2) nutritional messaging, (3) non-nutritional messaging, (4) endcaps and secondary placement, (5) point-of-sale interventions, (6) increased stocking, (7) food tasting and demonstrations, (8) nutrition education, and (9) placement on shelf interventions. Nutritional scoring and nutritional messaging emerged as the most rigorously tested and effective intervention strategies. Other strategies warrant more research attention. Simple intervention strategies, as opposed to complex ones, yield the most successful results and minimize shopper burden. Therefore, these strategies should be reviewed for policy implementation within SNAP-authorized grocery retailers.


Subject(s)
Consumer Behavior , Health Promotion , Health Promotion/methods , Beverages , Marketing , Food , Commerce
3.
Emerg Infect Dis ; 28(10): 2137-2139, 2022 10.
Article in English | MEDLINE | ID: mdl-36148986

ABSTRACT

We report a higher percentage of Sindbis virus-specific IgG in serum from patients attending a rheumatology clinic (18.8%) compared with healthy residents (9.6%) and patients with acute febrile illness (9.4%) in Free State Province, South Africa. Sindbis virus infection should be considered a potential cause of arthritis in South Africa.


Subject(s)
Antibodies, Viral , Sindbis Virus , Humans , Immunoglobulin G , Seroepidemiologic Studies , South Africa/epidemiology
4.
SLAS Discov ; 27(1): 8-19, 2022 01.
Article in English | MEDLINE | ID: mdl-35058179

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Cysteine Proteinase Inhibitors/pharmacology , Dipeptides/pharmacology , Virus Attachment/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cathepsin L/antagonists & inhibitors , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , HEK293 Cells , Humans , Molecular Docking Simulation , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
5.
Rural Remote Health ; 21(4): 6724, 2021 11.
Article in English | MEDLINE | ID: mdl-34753291

ABSTRACT

INTRODUCTION: Despite UN recommendations to monitor food insecurity using the Food Insecurity Experience Scale (FIES), to date there are no published reports of its validity for The Bahamas, nor have prevalence rates of moderate or severe food insecurity been reported for the remote island nation. At the same time, food security is a deep concern, with increasing incidence of natural disasters and health concerns related to diet-related disease and dietary quality plaguing the nation and its food system. This article aims to examine the validity of the FIES for use in The Bahamas, the prevalence of moderate and severe food insecurity, and the sociodemographic factors that contribute to increased food insecurity. METHODS: The FIES survey was administered by randomized and weighted landline telephone survey in Nassau in The Bahamas to 1000 participants in June and July 2017. The Rasch modelling procedure was applied to examine tool validity and prevalence of food insecurity. Equating procedures calibrated this study's results to the global FIES reference scale and computed internationally comparable prevalence rates of both moderate and severe food insecurity. A regression analysis assessed the relationship between household variables and food security. RESULTS: The FIES met benchmarks for fit statistics for all eight items and the overall Rasch reliability is 0.7. As of 2017, Bahamians' prevalence of moderate and severe food insecurity was 21%, and the prevalence of severe food insecurity was 10%. Statistically significant variables that contribute to food insecurity included education, age, gender, and presence of diabetes, high blood pressure, or heart disease. Results also indicated that Bahamians experience food insecurity differently than populations across the globe, likely due in large part to the workings of an isolated food system heavily dependent on foreign imports. Responses showed that by the time a Bahamian worries they will not have enough food to eat, they have already restricted their meals to a few kinds of foods and begun to limit their intake of vegetables and fruits. CONCLUSION: This study, which is among the first to comprehensively measure food security in The Bahamas, provides a baseline for further research and evaluation of practices aimed at mitigating food insecurity in small island developing states. Further, this study provides a benchmark for future research, which may seek to understand the impacts of Hurricane Dorian and COVID-19, disasters further isolating the remote island nation. Post-disaster food security data are needed to further understand the extent to which food security is impacted by natural disasters and identify which sectors and stakeholders are most vital in restructuring the agricultural sector and improving food availability following catastrophic events.


Subject(s)
Food Insecurity , Food Supply/statistics & numerical data , Hunger , Surveys and Questionnaires/standards , Bahamas , Humans , Prevalence , Reproducibility of Results , Socioeconomic Factors
6.
Proc Natl Acad Sci U S A ; 118(48)2021 11 30.
Article in English | MEDLINE | ID: mdl-34819362

ABSTRACT

The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein-biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein-signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.


Subject(s)
Receptors, G-Protein-Coupled/metabolism , Receptors, Opioid, mu/metabolism , Signal Transduction/drug effects , Analgesics, Opioid/pharmacology , Animals , Benzimidazoles/pharmacology , GTP-Binding Proteins/metabolism , Ligands , Male , Mice , Mice, Inbred C57BL , Narcotic Antagonists/pharmacology , Piperidines/pharmacology , Receptors, G-Protein-Coupled/physiology , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/physiology , Signal Transduction/physiology , beta-Arrestin 2/metabolism
7.
Neuropharmacology ; 185: 108439, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33345829

ABSTRACT

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over ßarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.


Subject(s)
Analgesics, Opioid/administration & dosage , Benzimidazoles/administration & dosage , Morphine/administration & dosage , Neuralgia/drug therapy , Oxycodone/administration & dosage , Piperidines/administration & dosage , Receptors, Opioid, mu/agonists , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Tolerance , Female , Infusion Pumps, Implantable , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neuralgia/pathology , Pain Measurement/drug effects , Pain Measurement/methods , Treatment Outcome
8.
Prev Med Rep ; 20: 101272, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33354493

ABSTRACT

The consumption of sugar-sweetened beverages (SSBs) has been linked to obesity, diabetes, and other negative health outcomes among children. In response, many government entities have enacted healthy default beverage policies that require restaurants offering bundled kids' meals-food and drink items combined and sold as a single unit-to include only healthier drinks. Despite growing interest in these policies, little is known about their potential reach, restaurant management perceptions, and possible implementation challenges. This study evaluated restaurant managers' knowledge and support of a policy in Delaware that had passed, but not yet gone into effect. We conducted structured in-person interviews with managers (n = 50) from full-service and quick-service chain and non-chain restaurants (QSRs) using a stratified random sample. Managers were interviewed about the number of bundled meals sold, beverage sales with those meals, and awareness and perceptions of the policy. On average, QSRs sold significantly more bundled kids' meals per week (281) compared to full-service restaurants (111), and managers from chain restaurants reported selling significantly more bundled kids' meals per week (233) compared to non-chain restaurants (91). Managers reported 72.5% of those meals were sold with a healthier beverage (water, milk, or 100% juice), consistent with the forthcoming policy, while 28% were sold with SSBs. Furthermore, although only three managers (6%) reported knowing about the policy, the majority supported it when it was explained. Our findings indicate general support for the intent of the policy, but suggest the need for tailored implementation approaches and additional education for restaurant manager's and staff.

9.
Neuropsychopharmacology ; 45(2): 416-425, 2020 01.
Article in English | MEDLINE | ID: mdl-31443104

ABSTRACT

It has been demonstrated that opioid agonists that preferentially act at µ-opioid receptors to activate G protein signaling over ßarrestin2 recruitment produce antinociception with less respiratory suppression. However, most of the adverse effects associated with opioid therapeutics are realized after extended dosing. Therefore, we tested the onset of tolerance and dependence, and assessed for neurochemical changes associated with prolonged treatment with the biased agonist SR-17018. When chronically administered to mice, SR-17018 does not lead to hot plate antinociceptive tolerance, receptor desensitization in periaqueductal gray, nor a super-sensitization of adenylyl cyclase in the striatum, which are hallmarks of opioid neuronal adaptations that are seen with morphine. Interestingly, substitution with SR-17018 in morphine-tolerant mice restores morphine potency and efficacy, whereas the onset of opioid withdrawal is prevented. This is in contrast to buprenorphine, which can suppress withdrawal, but produces and maintains morphine antinociceptive tolerance. Biased agonists of this nature may therefore be useful for the treatment of opioid dependence while restoring opioid antinociceptive sensitivity.


Subject(s)
Analgesics, Opioid/metabolism , Drug Tolerance/physiology , Morphine Dependence/metabolism , Morphine/metabolism , Receptors, Opioid, mu/metabolism , Substance Withdrawal Syndrome/metabolism , Analgesics, Opioid/administration & dosage , Animals , Dose-Response Relationship, Drug , Female , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Infusion Pumps, Implantable , Male , Mice , Mice, Inbred C57BL , Morphine/administration & dosage , Oxycodone/administration & dosage , Oxycodone/metabolism , Pain Measurement/drug effects , Pain Measurement/methods , Receptors, Opioid, mu/agonists , Substance Withdrawal Syndrome/prevention & control
10.
J Telemed Telecare ; 26(1-2): 100-104, 2020.
Article in English | MEDLINE | ID: mdl-30235968

ABSTRACT

Introduction: The objective of this study is to compare the clinical outcomes of patients with varicose veins managed in the telemedicine clinic and traditional clinic. Methods: Retrospective analysis of all vein procedures in the institutional Vascular Quality Initiative Varicose Vein Registry (VQI VVR) was performed from January 2015 to August 2017. Patients were divided into two groups: Telemedicine versus Traditional Clinic. Comparison data included patient demographics, past medical history, clinical outcomes, patient-reported outcomes and postoperative complications. Statistical testing included chi-square test for categorical variables and student t-test for continuous variables using the SPSS statistical software. Results: A total of 1034 varicose vein procedures were performed during the 31-month study period. There were 75 virtual encounters in the Telemedicine Clinic (Group A) and 959 face-to-face encounters in the Traditional Clinic (Group B). Most of the demographics characteristics were clinically similar in both groups. Comparing Group A and Group B, there were no differences in age, sex, race and body mass index. Early 3-month follow up was 100% in Group A and 90.7% in Group B. Both groups had low complication rates of haematoma (1.3% vs 0.3%, p = 0.884), paraesthesia (1.3% vs 0.6%, p = 0.767) and recanalisation (1.3% vs 4.0%, p = 0.383) during the early follow up period. Discussion: Synchronous virtual visits for patient care are feasible for the management of chronic venous disease. Patients with varicose veins who choose to undergo telemedicine evaluations have similar pre-operative demographics, clinical classification and patient outcomes.


Subject(s)
Ambulatory Care Facilities/organization & administration , Telemedicine/organization & administration , Varicose Veins/therapy , Vascular Surgical Procedures/methods , Adult , Aged , Ambulatory Care Facilities/standards , Chronic Disease , Comorbidity , Female , Humans , Male , Middle Aged , Patient Reported Outcome Measures , Postoperative Complications/epidemiology , Retrospective Studies , Socioeconomic Factors , Telemedicine/standards , Vascular Surgical Procedures/adverse effects
11.
Sci Rep ; 9(1): 2933, 2019 02 27.
Article in English | MEDLINE | ID: mdl-30814527

ABSTRACT

Accurate fiber tip tracking is a critical clinical problem during endovenous laser ablation (EVLA) of small perforating veins. Currently, ultrasound (US) imaging is the gold-standard modality for visualizing and for accurately placing the ablation fiber within the diseased vein. However, US imaging has limitations such as angular dependency and comet tail artifacts. In addition, EVLA is often performed without any real-time temperature monitoring, which could lead to an insufficient thermal dose or overheating the surrounding tissue. We propose a new technique that combines US and photoacoustic (PA) imaging for concurrent ablation fiber tip tracking and real-time temperature monitoring during EVLA procedures. Our intended implementation of PA imaging for fiber tracking requires minimal modification of existing systems, which makes this technology easy to adopt. Combining US and PA imaging modalities allows for simultaneous visualization of background anatomical structures as well as high contrast, artifact-free, and angle-independent localization of the ablation fiber tip. Preliminary data demonstrates that changes in the amplitude of the PA signal can be used to monitor the localized temperature at the tip of the ablation fiber, which will be invaluable during EVLA procedures. These improvements can enhance the physician's accuracy in performing EVLA procedures and will have a significant impact on the treatment outcomes.


Subject(s)
Endovascular Procedures/methods , Laser Therapy/methods , Photoacoustic Techniques/methods , Varicose Veins/surgery , Humans , Lasers , Saphenous Vein/surgery , Surgery, Computer-Assisted/methods , Treatment Outcome
12.
J Med Chem ; 61(19): 8895-8907, 2018 10 11.
Article in English | MEDLINE | ID: mdl-30199635

ABSTRACT

While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal ßarrestin-mediated signaling because MOR agonist-treated ßarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/ßarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.


Subject(s)
Analgesics, Opioid/pharmacology , Blood-Brain Barrier/metabolism , Drug Discovery/standards , GTP-Binding Proteins/metabolism , Microsomes, Liver/metabolism , Receptors, Opioid, mu/agonists , Analgesics, Opioid/chemistry , Animals , Blood-Brain Barrier/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Protein Conformation , Structure-Activity Relationship , beta-Arrestins/metabolism
13.
J Vasc Surg Venous Lymphat Disord ; 6(6): 702-706, 2018 11.
Article in English | MEDLINE | ID: mdl-30064962

ABSTRACT

BACKGROUND: Risk factors for chronic venous disease (CVD) have been widely reported in population health management. However, predisposing factors associated with patients treated for advanced stages of CVD have yet to be established. We examined the demographics and risk factors associated with advanced clinical presentation of CVD for patients referred for vein ablation. METHODS: Retrospective analysis of our institutional Vascular Quality Initiative Varicose Vein Registry included endovenous laser treatment and radiofrequency ablation procedures at our tertiary institution, community hospital, and outpatient vein clinic between January 2015 and December 2016. All incompetent truncal veins were divided into two groups based on the Clinical, Etiology, Anatomy, and Pathophysiology clinical class of CVD: mild-moderate (C1-C3) and severe (C4-C6). The two groups were compared in terms of their demographics and medical comorbidities using univariate and multivariate analysis. Data analysis was conducted on SPSS 22.0 (IBM Corp, Armonk, NY). RESULTS: During the study period, a total of 650 incompetent truncal veins were ablated. The mean age of patients was 58 years, and 73% were female. Severe CVD composed 21% of the cohort. Male sex was a risk for advanced CVD (odds ratio, 2.6; P < .001). Older age was also associated with severe CVD; the average age was 63 years for patients with advanced stage CVD vs 56 years for mild to moderate CVD (P < .001). Race, diabetes, body mass index, number of pregnancies, congestive heart failure, history of venous thromboembolism, current anticoagulation, and history of smoking or current smoking status did not affect the severity of CVD. CONCLUSIONS: Among patients treated with vein ablation for superficial venous insufficiency, older age and male sex were associated with increased severity of advanced CVD. Despite the higher incidence of varicose veins among women, men are more likely to have clinically advanced CVD when they present for truncal vein ablation.


Subject(s)
Varicose Veins/epidemiology , Venous Insufficiency/epidemiology , Age Factors , Catheter Ablation , Chronic Disease , Female , Humans , Incidence , Laser Therapy , Male , Michigan/epidemiology , Middle Aged , Registries , Retrospective Studies , Risk Factors , Severity of Illness Index , Sex Factors , Varicose Veins/diagnostic imaging , Varicose Veins/surgery , Venous Insufficiency/diagnostic imaging , Venous Insufficiency/surgery
14.
Assay Drug Dev Technol ; 16(5): 278-288, 2018 07.
Article in English | MEDLINE | ID: mdl-30019946

ABSTRACT

GPR119 drug discovery efforts in the pharmaceutical industry for the treatment of type 2 diabetes mellitus (T2DM) and obesity, were initiated based on its restricted distribution in pancreas and GI tract, and its possible role in glucose homeostasis. While a number of lead series have emerged, the pharmacological endpoints they provide have not been clear. In particular, many lead series have demonstrated loss of efficacy and significant toxic side effects. Thus, we sought to identify novel, potent, positive modulators of GPR119. In this study, we have successfully developed and optimized a high-throughput screening strategy to identify GPR119 modulators using a live cell assay format that utilizes a cyclic nucleotide-gated channel as a biosensor for cAMP production. Our high-throughput screening (HTS) approach is unique to that of previous HTS approaches targeting this receptor, as changes in cAMP were measured both in the presence and absence of an EC10 of the endogenous ligand, oleoylethanolamide, enabling detection of both agonists and potential allosteric modulators in a single assay. From these efforts, we have identified positive modulators of GPR119 with similar as well as unique scaffolds compared to existing compounds and similar as well as unique signaling properties. Our compounds will not only serve as novel molecular probes to better understand GPR119 pleiotropic signaling and the underlying physiological consequences of receptor activation, but are also well-suited for translation as potential therapeutic agents.


Subject(s)
Endocannabinoids/pharmacology , Hypoglycemic Agents/pharmacology , Oleic Acids/pharmacology , Receptors, G-Protein-Coupled/agonists , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Cells, Cultured , Endocannabinoids/chemistry , HEK293 Cells , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/chemistry , Molecular Structure , Oleic Acids/chemistry , Receptors, G-Protein-Coupled/metabolism
15.
Cell ; 171(5): 1165-1175.e13, 2017 Nov 16.
Article in English | MEDLINE | ID: mdl-29149605

ABSTRACT

Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit ßarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that ßarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.


Subject(s)
Analgesics, Opioid/administration & dosage , Analgesics, Opioid/adverse effects , Receptors, Opioid, mu/agonists , Animals , Fentanyl/administration & dosage , GTP-Binding Proteins/metabolism , Mice , Morphine/administration & dosage , Receptors, Opioid, mu/chemistry , Respiratory System/drug effects , Signal Transduction , beta-Arrestins/metabolism
16.
J Food Prot ; 79(7): 1259-65, 2016 07.
Article in English | MEDLINE | ID: mdl-27357048

ABSTRACT

Contamination by and persistence of pathogenic bacteria in ready-to-eat produce have emerged as significant food safety and public health concerns. Viable produceborne pathogens cope with several stresses (e.g., temperature fluctuations and lowtemperature storage) during production and storage of the commodities. In this study, we investigated the impact of transient cold shock on Escherichia coli O157:H7 (EcO157) cells in a produce matrix (romaine lettuce leaf lysate). EcO157 cells were exposed to 25°C for 1 h, 4°C for 1 h, and 4°C for 10 min in lettuce lysate. The expression of selected genes coding for virulence, stress response, and heat and cold shock proteins was quantified by real-time quantitative reverse transcription PCR assay. Treated EcO157 cells adhered to MAC-T mammalian cells were enumerated by in vitro bioassay. Expression of the Shiga toxin 1 gene (stx1a) was upregulated significantly (P < 0.05) upon cold shock treatments, but virulence genes related to EcO157 attachment (eaeA, lpfA, and hcpA) were down-regulated. Two key members of the cold shock regulon, cold shock protein (cspA) and gyrA, were significantly induced (P < 0.05) at the refrigeration temperature (4°C). Significant upregulation of an SOS response gene, recA, was also observed. E. coli heat shock regulon member grpE was induced, but a universal stress protein (uspA) was downregulated at the refrigeration temperatures in lettuce lysate. The adhesion assay revealed a temperature-dependent reduction in the attachment of cold-shocked EcO157 cells. The results of the current study indicate a reduction in the attachment of cold-shocked EcO157 to epithelial cells and higher levels of Shiga toxin gene expression at the molecular level.


Subject(s)
Escherichia coli O157 , Lactuca/microbiology , Animals , Colony Count, Microbial , Food Microbiology , Plant Leaves/microbiology , Shiga Toxin 1 , Virulence
17.
Angew Chem Int Ed Engl ; 55(1): 383-6, 2016 Jan 04.
Article in English | MEDLINE | ID: mdl-26577387

ABSTRACT

The reductive lithiation of phenyl thioethers, or alkyl chlorides, by either preformed aromatic radical anions or by lithium metal and an aromatic electron-transfer catalyst, is commonly used to prepare organolithiums. Revealed herein is that these two methods are fundamentally different. Reductions with radical anions occur in solution, whereas the catalytic reaction occurs on the surface of lithium, which is constantly reactivated by the catalyst, an unconventional catalyst function. The order of relative reactivity is reversed in the two methods as the dominating factor switches from electronic to steric effects of the alkyl substituent. A catalytic amount of N,N-dimethylaniline (DMA) and Li ribbon can achieve reductive lithiation. DMA is significantly cheaper than alternative catalysts, and conveniently, the Li ribbon does not require the removal of the oxide coating when DMA is used as the catalyst.

18.
J Org Chem ; 80(17): 8571-82, 2015 Sep 04.
Article in English | MEDLINE | ID: mdl-26225894

ABSTRACT

One of the most widely used methods of preparation of organolithium compounds is by the reductive lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides with either aromatic radical-anions of lithium or lithium metal in the presence of an aromatic electron-transfer catalyst. Here we present results showing that lithium dispersion can achieve reductive lithiation in the absence of the electron-transfer agent. This procedure is more efficient, and surprisingly, the order of reactivity of substrates is reversed depending on whether the electron-transfer agent is present or absent. For example, in the presence of a preformed radical-anion, tert-butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the absence of the radical-anion, it is just the opposite. Density functional theory calculations reveal that the exothermicity of the cleavage of the C-S bond in alkyl phenyl thioethers on the lithium surface is dependent on the size of the alkyl group, the smaller the alkyl group the greater the exothermicity. The increased reactivity is attributed to the smaller steric repulsion between the alkyl group and the lithium surface. The methodology includes, but may not be limited to, the lithium dispersion reductive lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and isochroman.

19.
J Org Chem ; 80(16): 8134-41, 2015 Aug 21.
Article in English | MEDLINE | ID: mdl-26226182

ABSTRACT

A simple method is presented for the highly stereoselective reductions of ketones to the most thermodynamically stable alcohols. In this procedure, the ketone is treated with lithium dispersion and either FeCl2·4H2O or CuCl2·2H2O in THF at room temperature. This protocol is applied to a large number and variety of ketones and is both more convenient and efficient than those commonly reported for the diastereoselective reduction of five- and six-membered cyclic ketones.

20.
Am J Surg ; 199(3): 369-71; discussion 371, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20226912

ABSTRACT

BACKGROUND: This study evaluates the relationship between body mass index (BMI) and other comorbidities on the overall morbidity and mortality of abdominal aortic aneurysm (AAA) repair. METHODS: A database of all nonemergent open and endovascular AAA repairs performed at our center from 2004 to 2008 was created. The outcomes at the predefined time intervals were then evaluated for each group of patients. RESULTS: One hundred forty-three patients qualified for this study with a 3:2 stent graft-to-open ratio. A trend relating patient BMI with early mortality was noted. Age>80 years was a strong predictor of mortality in all time intervals. CONCLUSIONS: The outcomes for this population show a significant trend toward early mortality in open AAA repair patients with an elevated preoperative BMI. Appropriate patient selection and preoperative optimization are recommended for all AAA repair candidates; however, some innate characteristics such as patient age, may play the largest role in determining outcomes.


Subject(s)
Aortic Aneurysm, Abdominal/surgery , Body Mass Index , Postoperative Complications/epidemiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Postoperative Complications/mortality , Retrospective Studies
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