• 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.
    • Evolution of our understanding of cell volume regulation by the pump-leak mechanism

      Kay, A.R.; Blaustein, M.P. (Rockefeller University Press, 2019)
      All animal cells are surrounded by a flexible plasma membrane that is permeable to water and to small ions. Cells thus face a fundamental problem: the considerable tension that their membranes would experience if the osmotic influx of water, driven by the presence of impermeant intracellular ions, was left unopposed. The pivotal study that described the cell's remedy for this impending osmotic catastrophe-the "pump-leak mechanism" (PLM)-was published in the Journal of General Physiology by Tosteson and Hoffman in 1960. Their work revealed how the sodium pump stabilizes cell volume by eliminating the osmotic gradient. Here we describe the mechanistic basis of the PLM, trace the history of its discovery, and place it into the context of our current understanding.
    • The hERG potassium channel intrinsic ligand regulates N- and C-terminal interactions and channel closure

      Codding, S.J.; Trudeau, M.C. (Rockefeller University Press, 2019)
      Human ether-à-go-go–related gene (hERG, KCNH2) voltage-activated potassium channels are critical for cardiac excitability. hERG channels have characteristic slow closing (deactivation), which is auto-regulated by a direct interaction between the N-terminal Per-Arnt-Sim (PAS) domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). hERG channels are not activated by the binding of extrinsic cyclic nucleotide ligands, but rather bind an “intrinsic ligand” that is composed of residues 860–862 within the CNBHD and mimics a cyclic nucleotide. The intrinsic ligand is located at the PAS–CNBHD interface, but its mechanism of action in hERG is not well understood. Here we use whole-cell patch-clamp electrophysiology and FRET spectroscopy to examine how the intrinsic ligand regulates gating. To carry out this work, we coexpress PAS (a PAS domain fused to cyan fluorescent protein) in trans with hERG “core” channels (channels with a deletion of the PAS domain fused to citrine fluorescent protein). The PAS domain in trans with hERG core channels has slow (regulated) deactivation, like that of WT hERG channels, as well as robust FRET, which indicates there is a direct functional and structural interaction of the PAS domain with the channel core. In contrast, PAS in trans with hERG F860A core channels has intermediate deactivation and intermediate FRET, indicating perturbation of the PAS domain interaction with the CNBHD. Furthermore, PAS in trans with hERG L862A core channels, or PAS in trans with hERG F860G,L862G core channels, has fast (nonregulated) deactivation and no measurable FRET, indicating abolition of the PAS and CNBHD interaction. These results indicate that the intrinsic ligand is necessary for the functional and structural interaction between the PAS domain and the CNBHD, which regulates the characteristic slow deactivation gating in hERG channels.
    • Future Directions for Research on Human-Animal Interaction in an Aging Population

      Gee, N.R.; Galik, E. (Taylor and Francis Ltd., 2019)
      This final paper in the thematic issue, “Human–Animal Interaction and Healthy Human Aging,” highlights and distills key points from the series of papers and provides recommendations for improving and expanding Human–Animal Interaction (HAI) research into healthy human aging. This paper also focuses on translating research to practice and discussing important practical issues related to pet ownership or interaction with companion animals among older adults, and makes specific recommendations for researchers, caregivers, and professionals working with older adults. In addition to issues related to the human side of the equation, we make recommendations for protecting and insuring the health and wellbeing of the animals involved.
    • Molecular Structure of the PKD Protein Complex Finally Solved

      Woodward, O.M.; Watnick, T. (W.B. Saunders, 2019)
    • To sleep or not to sleep

      Ehret, M.J. (Wiley-Blackwell, 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.
    • Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

      Underhill, S.M.; Rizzo, M.A.; Ingram, S.L. (Nature Publishing Group, 2019)
      The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
    • Correlates of reported modern contraceptive use among postpartum HIV-positive women in rural Nigeria: An analysis from the MoMent prospective cohort study

      Chinaeke, E.E.; Fan-Osuala, C.; Bathnna, M. (BioMed Central Ltd., 2019)
      Background: Nigeria has an annual population of ~ 200,000 women who are both pregnant and HIV-positive. High unmet need for family planning in this population could lead to unintended pregnancies, along with the increased risk of mother-to-child transmission of HIV (MTCT). To identify modifiable barriers and facilitators in effective family planning, we examined correlates of modern contraceptive use among HIV-positive women enrolled in the MoMent prevention of MTCT (PMTCT) implementation research study in rural North-Central Nigeria. Methods: In this prospective cohort study, HIV-positive pregnant women were enrolled at 20 Primary Healthcare Centers and followed up to 12 months postpartum. Baseline socio-demographic, clinical and obstetric data were collected at enrollment. Participants were to receive routine family planning counselling from healthcare workers during postnatal visits. Analysis utilized baseline data linked to available family planning information collected from each woman at the first postpartum visit. Multivariate logistic regression was performed to determine factors associated with modern contraceptive use. Results: Out of 497 women enrolled, family planning data was available for 399 (80.3%) women, of whom 349 (87.5%) received family planning counselling, and 321 (80.5%) were 30 years old or less. Two-thirds (268, 67.2%) of the cohort analyzed had 1-2 children at baseline; 24.8% (n = 99) had 3-4 children, and 8.0% (n = 32) had > 4 children. Approximately half (199, 49.9%) of the women reported no modern contraceptive use in the postpartum period. Male condoms (116, 29.1%) were the most reported method of contraception; other methods reported included oral hormones (71, 17.8%) and intrauterine devices (13, 3.2%). Only disclosure of HIV status to male partner or relative (aOR = 2.0, 95% CI: 1.2-3.3; p = 0.01) and receipt of family planning counselling (aOR = 2.3, 95% CI: 1.1-4.8; p = 0.03) were positively associated with reported modern contraceptive use. Age, marital or educational status, religious affiliation, employment status, gravidity and parity were non-correlates. Conclusions: Family planning counselling and disclosure of HIV status are modifiable positive predictors of contraceptive use among our cohort of postpartum HIV-positive women in rural Nigeria. Rates of unintended pregnancy and concomitant risk of MTCT could be significantly reduced through strategies that facilitate these correlates. Clinical trials registration: Clinicaltrials.gov registration number: NCT 01936753; registered September 3, 2013. © 2019 The Author(s).
    • Benign tumors in myotonic dystrophy type I target disease-related cancer sites

      Alsaggaf, R.; Zhan, M.; St. George, D.M.M. (Wiley-Blackwell, 2019)
      Objectives: Recent evidence showed that myotonic dystrophy type I (DM1) patients are at increased risk of certain cancers, but the risk of benign tumors is unknown. We compared the risk of benign tumors in DM1 patients with matched DM1-free individuals and assessed the association between benign tumors and subsequent cancers. Methods: We identified 927 DM1 patients and 13,085 DM1-free individuals matched on gender, birth-year, clinic, and clinic-registration year from the UK Clinical Practice Research Datalink, a primary care records database. We used Cox regression models for statistical analyses. Results: DM1 patients had elevated risks of thyroid nodules (Hazard Ratio [HR] = 10.4; 95% Confidence Interval [CI] = 3.91–27.52; P < 0.001), benign tumors of the brain or nervous system (HR = 8.4; 95% CI = 2.48–28.47; P < 0.001), colorectal polyps (HR = 4.3; 95% CI = 1.76–10.41; P = 0.001), and possibly uterine fibroids (HR = 2.7; 95% CI = 1.22–5.88; P = 0.01). Pilomatricomas and salivary gland adenomas occurred almost exclusively in DM1 patients (Fisher's exact P < 0.001). The HR for colorectal polyps was elevated in DM1 males but not in females (HR = 8.2 vs. 1.3, respectively; P-heterogeneity < 0.001), whereas endocrine and brain tumors occurred exclusively in females. The data suggested an association between benign tumors and subsequent cancer in classic DM1 patients (HR = 2.7; 95% CI = 0.93–7.59; P = 0.07). Interpretation: Our study showed a similar site-specific benign tumor profile to that previously reported for DM1-associated cancers. The possible association between benign tumors and subsequent cancer in classic DM1 patients warrants further investigation as it may guide identifying patients at elevated risk of cancer. Our findings underscore the importance of following population-based screening recommendations in DM1 patients, for example, for colorectal cancer. Copyright 2019 The Authors.
    • Genome Sequences and Methylation Patterns of Natrinema versiforme BOL5-4 and Natrinema pallidum BOL6-1, Two Extremely Halophilic Archaea from a Bolivian Salt Mine

      DasSarma, P.; Anton, B.P.; DasSarma, S.L.; Martinez, F.L.; DasSarma, S. (American Society for Microbiology, 2019)
      Two extremely halophilic archaea, namely, Natrinema versiforme BOL5-4 and Natrinema pallidum BOL6-1, were isolated from a Bolivian salt mine and their genomes sequenced using single-molecule real-time sequencing. The GC-rich genomes of BOL5-4 and BOL6-1 were 4.6 and 3.8 Mbp, respectively, with large chromosomes and multiple megaplasmids. Genome annotation was incorporated into HaloWeb and methylation patterns incorporated into REBASE. Copyright 2019 DasSarma et al.
    • Staphylococcus aureus-induced endothelial permeability and inflammation are mediated by microtubule destabilization

      Karki, P.; Ke, Y.; Tian, Y. (American Society for Biochemistry and Molecular Biology, 2019)
      Staphylococcus aureus is a major etiological agent of sepsis and induces endothelial cell (EC) barrier dysfunction and inflammation, two major hallmarks of acute lung injury. However, the molecular mechanisms of bacterial pathogen-induced EC barrier disruption are incompletely understood. Here, we investigated the role of microtubules (MT) in the mechanisms of EC barrier compromise caused by heat-killed S. aureus (HKSA). Using a customized monolayer permeability assay in human pulmonary EC and MT fractionation, we observed that HKSA-induced barrier disruption is accompanied by MT destabilization and increased histone deacetylase-6 (HDAC6) activity resulting from elevated reactive oxygen species (ROS) production. Molecular or pharmacological HDAC6 inhibition rescued barrier function in HKSA-challenged vascular endothelium. The HKSA-induced EC permeability was associated with impaired MT-mediated delivery of cytoplasmic linker-associated protein 2 (CLASP2) to the cell periphery, limiting its interaction with adherens junction proteins. HKSA-induced EC barrier dysfunction was also associated with increased Rho GTPase activity via activation of MT-bound Rho-specific guanine nucleotide exchange factor-H1 (GEF-H1) and was abolished by HDAC6 down-regulation. HKSA activated the NF-κB proinflammatory pathway and increased the expression of intercellular and vascular cell adhesion molecules in EC, an effect that was also HDAC6-dependent and mediated, at least in part, by a GEF-H1/Rho-dependent mechanism. Of note, HDAC6 knockout mice or HDAC6 inhibitor-treated WT mice were partially protected from vascular leakage and inflammation caused by both HKSA or methicillin-resistant S. aureus (MRSA). Our results indicate that S. aureus-induced, ROS-dependent up-regulation of HDAC6 activity destabilizes MT and thereby activates the GEF-H1/Rho pathway, increasing both EC permeability and inflammation. © 2019 Karki et al.
    • Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice

      Feng, Y.; Xie, Y.; Li, L. (American Society for Biochemistry and Molecular Biology Inc., 2019)
      Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo. We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients May have heightened sensitivity to CEEs due to the inflammatory induction of STS activity. Copyright 2019 Feng et al.
    • Microbial Profile and Endotoxin Levels in Primary Periodontal Lesions with Secondary Endodontic Involvement

      Martinho, F.C.; da Silva Rovai, E.; de Souza Matos, F. (NLM (Medline), 2019)
      This study was carried out to investigate the microbial profile and endotoxin levels of endodontic-periodontal lesions of periodontal origin. Periodontal and endodontic samples were taken from periodontal pockets and necrotic root canals of 10 teeth with endodontic-periodontal lesions. Evidencing of 40 different bacterial species were determined in each endodontic and periodontal sample using the checkerboard DNA-DNA hybridization method and Kinetic chromogenic LAL assay was used for quantification of endotoxins. Fisher's exact test correlated the bacterial species with the endodontic or periodontal microbiota. The endotoxin levels (EU/mL) found in samples of the root canal and periodontal pocket were compared by the Wilcoxon test (p<0.05). Bacteria and LPS units were found in 100% of the endodontic and periodontal samples. The species E. faecium, P. acnes, G. morbillorum, C. sputigena and L. buccalis were strongly correlated with the endodontic microbiota and P. nigrescens with the periodontal microbiota. P. intermedia, P. endodontalis and V. parvula were more prevalent in both endodontic and periodontal microbiots. The endotoxin levels in the periodontal pocket (89600 EU/mL) were significantly higher than in the root canal (2310 EU/mL). It was concluded that the microbiota present in the periodontal and endodontic tissues is similar, with a higher prevalence of species of the orange complex and a higher level of endotoxin in the periodontal pockets.