• 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: 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: 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: 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.
    • 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.
    • A promiscuous kinase inhibitor reveals secrets to cancer cell survival

      Shapiro, P. (American Society for Biochemistry and Molecular Biology Inc., 2019)
      Deregulated kinase signaling networks drive the growth and survival of many cancer cells. However, the genetic complexity and rapidly evolving nature of most cancer cells create challenges when identifying the most relevant kinases to inhibit to achieve optimal therapeutic benefits. A new strategy that takes advantage of a well-characterized multitargeted kinase inhibitor describes a nongenetic approach to tease out key kinases that promote proliferation of specific cancer cell types. Copyright 2019 Shapiro.
    • Plasma for burn shock resuscitation: is it time to go back to the future?

      Gurney, J.M.; Kozar, R.A.; Cancio, L.C. (Blackwell Publishing Inc., 2019)
      Patients with burn shock can be challenging to resuscitate. Burn shock produces a variety of physiologic derangements: Patients are hypovolemic from volume loss, have a increased systemic vascular resistance, and may have a depressed cardiac output depending on the extent of the thermal injury. Additionally, the burn wound produces a significant inflammatory cascade of events that contributes to the shock state. Fluid resuscitation is foundational for the initial treatment of burn shock. Typical resuscitation is with intravenous lactated Ringer's in accordance with well-established formulas based on burn wound size. In the past century, as therapies to treat thermal injuries were being developed, plasma was the fluid used for burn resuscitation; in fact, plasma was used in World War II and throughout the 1950s and 1960s. Plasma was abandoned because of infectious risks and complications. Despite huge strides in transfusion medicine and the increased safety of blood products, plasma has never been readopted for burn resuscitation. Over the past 15 years, there has been a paradigm shift in trauma resuscitation: Less crystalloid and more blood products are used; this strategy has demonstrated improved outcomes. Plasma is a physiologic fluid that stabilizes the endothelium. The endotheliopathy of trauma has been described and is mitigated by transfusion strategies with a 1:1 ratio of RBCs to plasma. Thermal injury also results in endothelial dysfunction: the endotheliopathy of burns. Plasma is likely a better resuscitation fluid for patients with significant burn wounds because of its capability to restore intravascular volume status and treat the endotheliopathy of burns.
    • Circulating and circular RNAs and the need for rationalization and synthesis of the research spiral

      Dvorak, P.; Leupen, S.; Soucek, P. (Wroclaw Medical University Press, 2019)
      In this essay, we aim to draw a short comparison between 2 important research topics - circular and circulating RNAs - and show how they are connected. The findings described here in the field of circular RNAs, which are still quite obscured by the rapidly expanding body of knowledge in biology, have added another dimension to our view of the process of gene expression, which is formed by a more complex network of molecule interactions than we previously thought. The term "circulating RNAs" refers to a broad spectrum of RNA fragments originating from different sources, such as physiologically dying cells, sites of inflammation or cancer cells, and fragments floating in human liquid tissues together with other elements. Fragments of nucleic acids circulating in blood are emerging as promising biomarkers in different medical conditions. Interestingly, circular RNAs have been found to be present in human blood and form a fraction of circulating RNAs. In addition to updating readers on these fast-developing areas of biology, we also stress the need for the study of complex networks of molecule interactions as whole structures (in unison with the thoughts of systems biology), as opposed to the trend toward searching for individual key player molecules. Fundamentally, we want to add to the rationalization and synthesis of new research findings in the scientific literature, because this direction is important not only for students, teachers and researchers, but also for the general population.
    • Fetal Programming and Sexual Dimorphism of Mitochondrial Protein Expression and Activity of Hearts of Prenatally Hypoxic Guinea Pig Offspring

      Thompson, L.P.; Song, H.; Polster, B.M. (Hindawi, 2019)
      Chronic intrauterine hypoxia is a programming stimulus of cardiovascular dysfunction. While the fetal heart adapts to the reduced oxygenation, the offspring heart becomes vulnerable to subsequent metabolic challenges as an adult. Cardiac mitochondria are key organelles responsible for an efficient energy supply but are subject to damage under hypoxic conditions. We propose that intrauterine hypoxia alters mitochondrial function as an underlying programming mechanism of contractile dysfunction in the offspring. Indices of mitochondrial function such as mitochondrial DNA content, Complex (C) I-V expression, and CI/CIV enzyme activity were measured in hearts of male and female offspring at 90 days old exposed to prenatal hypoxia (10.5% O2) for 14 d prior to term (65 d). Both left ventricular tissue and cardiomyocytes exhibited decreased mitochondrial DNA content, expression of CIV, and CI/CIV activity in male hearts. In female cardiomyocytes, hypoxia had no effect on protein expression of CI-CV nor on CI/CIV activity. This study suggests that chronic intrauterine hypoxia alters the intrinsic properties of select respiratory complexes as a programming mechanism of cardiac dysfunction in the offspring. Sex differences in mitochondrial function may underlie the increased vulnerability of age-matched males compared to females in cardiovascular disease and heart failure.
    • Is routine genetic testing warranted in head and neck paragangliomas?

      Gupta, N.; Strome, S.E.; Hatten, K.M. (John Wiley and Sons Inc., 2019)
    • The Importance of Being Curious

      Adashi, E.Y.; Ahmed, A.-K.H.; Gruppuso, P.A. (Elsevier Inc., 2019)
    • Self-reported infertility, metabolic dysfunction, and cardiovascular events: a cross-sectional analysis among U.S. women

      Gleason, J.L.; Shenassa, E.D.; Thoma, M.E. (Elsevier Inc., 2019)
      Objective: To explore associations between infertility and metabolic syndrome, and cardiovascular events. Infertility is increasingly a public health issue, with emerging links to chronic disease. Existing literature on infertility focuses primarily on known causes, which likely excludes a substantial number of women for whom there is no known cause or formal diagnosis. Design/Setting: We conducted a cross-sectional analysis examining the association between self-reported infertility (i.e., ever experiencing inability to conceive after 12 months of trying to become pregnant) and metabolic syndrome and cardiovascular events (i.e., congestive heart failure, coronary heart disease, heart attack, or stroke). Data were analyzed using multivariate logistic regression. Patient(s): A total of 744 U.S. women, 20–59 years of age, from the National Health and Nutrition Examination Survey (2013–2014), participated in the study. Among them, 15.7% reported ever experiencing infertility, 27.6% met the definition of metabolic syndrome, and 2.84% reported ever having a cardiovascular event. Intervention(s): N/A. Main Outcome Measure(s): Metabolic syndrome and cardiovascular events. Results: Compared to women who had never experienced infertility, women who reported infertility had a 1.79 (95% confidence interval [CI] 1.04, 3.08) higher odds of reporting symptoms of metabolic syndrome and 1.83 (95% CI 1.15, 2.89) times higher odds of having experienced a cardiovascular event. Furthermore, women with self-reported infertility had a 71% higher odds of reporting a cardiovascular event after controlling for metabolic syndrome (95% CI 1.01, 3.00). Conclusions: Our results suggest that among U.S. women, the experience of infertility at any point in a woman's reproductive window may be associated with later-life cardiovascular health.
    • A Patient With Rectal Schwannoma

      Zibert, K.; Richards, S.; Darwin, P. (W.B. Saunders, 2019)
    • Serologic responses to the PfEMP1 DBL-CIDR head structure may be a better indicator of malaria exposure than those to the DBL-α tag

      Stucke, E.M.; Berry, A.A.; Ouattara, A.; Lyke, K.E.; Laurens, M.B.; Dara, A.; Adams, M.; Zhou, A.E.; Agrawal, S.; Friedman-Klabanoff, D.J.; et al. (BioMed Central Ltd., 2019)
      Background: Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion. Serologic responses to these antigens have been associated with protection from clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α "tag"). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. In this study, using sera from a malaria-endemic region, responses to DBL-α tags were compared to responses to the corresponding entire DBL-α domain (or "parent" domain) coupled with the succeeding cysteine-rich interdomain region (CIDR). Methods: A protein microarray populated with DBL-α tags, the parent DBL-CIDR head structures, and downstream PfEMP1 protein fragments was probed with sera from Malian children (aged 1 to 6 years) and adults from the control arms of apical membrane antigen 1 (AMA1) vaccine clinical trials before and during a malaria transmission season. Serological responses to the DBL-α tag and the DBL-CIDR head structure were measured and compared in children and adults, and throughout the season. Results: Malian serologic responses to a PfEMP1's DBL-α tag region did not correlate with seasonal malaria exposure, or with responses to the parent DBL-CIDR head structure in either children or adults. Parent DBL-CIDR head structures were better indicators of malaria exposure. Conclusions: Larger PfEMP1 domains may be better indicators of malaria exposure than short, variable PfEMP1 fragments such as DBL-α tags. PfEMP1 head structures that include conserved sequences appear particularly well suited for study as serologic predictors of malaria exposure. Copyright 2019 The Author(s).