• Catecholaminergic manipulation alters dynamic network topology across cognitive states

      Shine, J.M.; van den Brink, R.L.; Hernaus, D. (MIT Press Journals, 2017)
      The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.
    • Erratum: Author Correction: A population-specific reference panel empowers genetic studies of Anabaptist populations (Scientific reports (2017) 7 1 (6079))

      Hou, L.; Kember, R.L.; Roach, J.C.; O'Connell, J.R. (Springer Nature, 2018)
      A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
    • Erratum: Author Correction: Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis (Scientific reports (2017) 7 1 (1485))

      Li, N.; Xu, W.; Yuan, Y.; Ayithan, N. (NLM (Medline), 2018)
      A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper.
    • Erratum: Author Correction: Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL (Scientific reports (2018) 8 1 (744))

      Bhalla, K.; Jaber, S.; Nahid, N.; Underwood, K. (Springer Nature, 2018)
      A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
    • Use of clomiphene citrate alone, urinary follicle-stimulating hormone alone, or both combined sequentially in patients with unexplained subfertility undergoing intrauterine insemination: A randomized trial

      Ayaz, R.; Ayas, S.; Aşoglu, M.R. (Turkish Society of Obstetrics and Gynecology, 2018)
      Objective: To compare the successes of clomiphene citrate (CC) alone, pure human urinary follicle-stimulating hormone (uFSH) alone, and both combined sequentially in patients with unexplained subfertility couples undergoing intrauterine insemination (IUI). Materials and Methods: Patients aged 18-38 years who had a normal uterine cavity, at least one normal fallopian tube, and regular menses and were unable to conceive despite unprotected intercourse for at least 12 months were randomized to receive CC alone, uFSH alone, or sequential CC and uFSH before a single IUI. The primary outcomes were clinical pregnancy and live birth rates. The study was approved by the ethics committee of our institution. Results: A total of 135 patients were randomized, and 121 of these were able to complete the study. Of these, 30% (n=36) had CC alone, 34% (n=41) had uFSH alone, and 36% (n=44) had sequential CC and uFSH. The three groups did not significantly differ in terms of age, duration of infertility, hormone levels, and semen parameters. For CC alone, uFSH alone, and sequential CC plus uFSH groups, pregnancy rates were 8.3%, 17.1%, and 18.2%, respectively (p>0.05), and live birth rates were 8.3%, 12.1%, and 13.6%, respectively (p>0.05). Conclusion: In women with unexplained infertility, use of uFSH seemed to increase the success rate compared with CC alone. The sequential regime can significantly reduce the treatment cost if gonadotropin/IUI cycles are planned.
    • Dangerous parking deck

      Feliciano, D.V. (BMJ Publishing Group, 2019)
    • Alternate route

      Feliciano, D.V. (BMJ Publishing Group, 2019)
    • Why is clinical fMRI in a resting state?

      O'Connor, E.E.; Zeffiro, T.A. (Frontiers Media S.A., 2019)
      While resting state fMRI (rs-fMRI) has gained widespread application in neuroimaging clinical research, its penetration into clinical medicine has been more limited. We surveyed a neuroradiology professional group to ascertain their experience with rs-fMRI, identify perceived barriers to using rs-fMRI clinically and elicit suggestions about ways to facilitate its use in clinical practice. The electronic survey also collected information about demographics and work environment using Likert scales. We found that 90% of the respondents had adequate equipment to conduct rs-fMRI and 82% found rs-fMRI data easy to collect. Fifty-nine percent have used rs-fMRI in their past research and 72% reported plans to use rs-fMRI for research in the next year. Nevertheless, only 40% plan to use rs-fMRI in clinical practice in the next year and 82% agreed that their clinical fMRI use is largely confined to pre-surgical planning applications. To explore the reasons for the persistent low utilization of rs-fMRI in clinical applications, we identified barriers to clinical rs-fMRI use related to the availability of robust denoising procedures, single-subject analysis techniques, demonstration of functional connectivity map reliability, regulatory clearance, reimbursement, and neuroradiologist training opportunities. In conclusion, while rs-fMRI use in clinical neuroradiology practice is limited, enthusiasm appears to be quite high and there are several possible avenues in which further research and development may facilitate its penetration into clinical practice. Copyright Copyright 2019 O'Connor and Zeffiro.
    • Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer

      Xu, J.; Qiu, Y. (Wolters Kluwer Medknow Publications, 2019)
      Recent advances in genomics technology have led to the massive discovery of new drug targets for prostate cancer; however, none of the currently available therapeutics is curative. One of the greatest challenges is drug resistance. Combinations of therapies with distinct mechanisms of action represent a promising strategy that has received renewed attention in recent years. Combination therapies exert cancer killing functions through either concomitant targeting of multiple pro-cancer factors or more effective inhibition of a single pathway. Theoretically, the combination therapy can improve efficacy and efficiency compared with monotherapy. Although increasing numbers of drug combinations are currently being tested in clinical trials, the mechanisms by which these combinations can overcome drug resistance have yet to be fully understood. The purpose of this review is to summarize recent work on therapeutic combinations in the treatment of castration-resistant prostate cancer and discuss emerging mechanisms underlying drug resistance. In addition, we provide an overview of the current preclinical mechanistic studies on potential therapeutic combinations to overcome drug resistance. Copyright The Author(s)(2018).
    • Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy

      Ludman, T.; Melemedjian, O.K. (SAGE Publications Inc., 2019)
      Chemotherapy-induced painful peripheral neuropathy is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which chemotherapy-induced painful peripheral neuropathy develops have remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha is a transcription factor that is known to reprogram cellular metabolism. Furthermore, hypoxia-inducible factor 1 alpha protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilizes the expression of hypoxia-inducible factor 1 alpha leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilizes the expression of hypoxia-inducible factor 1 alpha. Moreover, knockdown of hypoxia-inducible factor 1 alpha, inhibition of hypoxia-inducible factor 1 alpha binding to its response element, or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of hypoxia-inducible factor 1 alpha expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of hypoxia-inducible factor 1 alpha expression as the molecular mechanism by which bortezomib initiates chemotherapy-induced painful peripheral neuropathy. Crucially, these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms. Copyright The Author(s) 2019.
    • Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

      Ludman, T.; Melemedjian, O.K. (SAGE Publications Inc., 2019)
      Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN. Copyright The Author(s) 2019.
    • Accumbal Dopamine Release Tracks the Expectation of Dopamine Neuron-Mediated Reinforcement

      Covey, D.P.; Cheer, J.F. (Elsevier B.V., 2019)
      Dopamine (DA) transmission in the nucleus accumbens (NAc) facilitates cue-reward associations and appetitive action. Reward-related accumbal DA release dynamics are traditionally ascribed to ventral tegmental area (VTA) DA neurons. Activation of VTA to NAc DA signaling is thought to reinforce action and transfer reward-related information to predictive cues, allowing cues to guide behavior and elicit dopaminergic activity. Here, we use optogenetics to control DA neuron activity and voltammetry to simultaneously record accumbal DA release in order to quantify how reinforcer-evoked dopaminergic activity shapes conditioned mesolimbic DA transmission. We find that cues predicting access to DA neuron self-stimulation elicit conditioned responding and NAc DA release. However, cue-evoked DA release does not reflect the cost or magnitude of DA neuron activation. Accordingly, conditioned accumbal DA release selectively tracks the expected availability of DA-neuron-mediated reinforcement. This work provides insight into how mesolimbic DA transmission drives and encodes appetitive action. To understand how mesolimbic dopamine signaling drives and encodes reward learning and seeking, Covey and Cheer recorded nucleus accumbens dopamine release while mice performed optogenetic self-stimulation of dopamine neurons. Cues that motivated self-stimulation elicited dopamine release, which reflected the availability, but not the expected cost or magnitude, of dopamine neuron activation. Copyright 2019 The Author(s)
    • Stability of individual differences in sucralose taste preference

      Bacharach, S.Z.; Calu, D.J. (Public Library of Science, 2019)
      Outbred rats display variable preferences for bittersweet solutions, expressed as preference or avoidance of high concentrations of artificial sweeteners over water. This may reflect individual differences in appetitive/aversive conflict processing that may have predictive validity for disorders of motivation. Here we use a homecage two-bottle choice procedure to examine the test/retest stability and between-tastant consistency in sucralose preference to determine the reliability of bittersweet taste preference. Sucralose is a non-caloric artificial sweetener that is preferred by some rats and avoided by others. We sought to determine whether sucralose preference is consistent with preference of sucrose/quinine solutions that have known sweet and bitter taste qualities, respectively. We give fluid restricted rats 45-minutes homecage access to water and ascending concentrations of sucralose (SUCRA; 0.0025-10mM) or a compound solution of sucrose (116mM) + quinine (0.002-2mM) (SQ). We use a within-subject counterbalanced design (SUCRA or SQ testing) to determine preference of each bittersweet solution relative to water. We observed individual variability in preference for SUCRA and SQ, such that some rats preferred bittersweet solutions over water (preferring) while other rats preferred water over bittersweet solutions (avoiding). Within tastant, this preference remained stable across repeated testing. Between solutions, SUCRA preference scores correlated with SQ scores, suggesting consistent taste conflict processing for both bittersweet solutions. Population level analyses confirmed that preference generalizes across bittersweet solutions, and that rats' preferences for bittersweet solutions relative to water are stable over time. The test/retest and between-tastant reliability of this taste conflict screening procedure support the potential utility of this model for exploring individual variability in appetitive/aversive conflict processes mediating motivated behavior. Copyright 2019 Bacharach, Calu.
    • Integration of Simulation to Prepare Adult-Gerontology Acute Care Nurse Practitioners

      Schneidereith, T.; Daniels, A. (Elsevier Inc., 2019)
      Background: The nation's demographics and health care needs are changing, concurrent with the demand to double the number of doctorally prepared nurses by 2020. This combination has intensified challenges associated with finding quality clinical placements and appropriate preceptors for nurse practitioner (NP) students. Purposefully integrated simulations offer alternate experiences and expose students to deliberately crafted and consistent learning opportunities. Methods: Scaffolded simulations were integrated within an Adult-Gerontology Acute Care Nurse Practitioner Program over the course of six semesters. Results: Analysis is currently underway, but preliminary data show that simulation experiences helped to develop assessment, critical thinking, and decision-making skills. The students also felt better prepared to communicate with other health care providers in this new role. Conclusion: Although resource intensive, simulation provides an unparalleled opportunity for NP students to independently perform, without direct supervision, as an NP. Presenting an example of simulation integration can aid other educators seeking to develop a similar program.
    • Is routine genetic testing warranted in head and neck paragangliomas?

      Gupta, N.; Strome, S.E.; Hatten, K.M. (John Wiley and Sons Inc., 2019)