MSTPublications: August 2022
Uropathogenic Escherichia coli subverts mitochondrial metabolism to enable intracellular bacterial pathogenesis in urinary tract infection.
Beebout CJ, Robertson GL, Reinfeld BI, Blee AM, Morales GH, Brannon JR, Chazin WJ, Rathmell WK, Rathmell JC, Gama V, Hadjifrangiskou M.
Nat Microbiol. 2022 Sep;7(9):1348-1360. doi: 10.1038/s41564-022-01205-w. Epub 2022 Aug 22.
Urinary tract infections are among the most common human bacterial infections and place a significant burden on healthcare systems due to associated morbidity, cost and antibiotic use. Despite being a facultative anaerobe, uropathogenic Escherichia coli, the primary cause of urinary tract infections, requires aerobic respiration to establish infection in the bladder. Here, by combining bacterial genetics with cell culture and murine models of infection, we demonstrate that the widely conserved respiratory quinol oxidase cytochrome bd is required for intracellular infection of urothelial cells. Through a series of genetic, biochemical and functional assays, we show that intracellular oxygen scavenging by cytochrome bd alters mitochondrial physiology by reducing the efficiency of mitochondrial respiration, stabilizing the hypoxia-inducible transcription factor HIF-1 and promoting a shift towards aerobic glycolysis. This bacterially induced rewiring of host metabolism antagonizes apoptosis, thereby protecting intracellular bacteria from urothelial cell exfoliation and preserving their replicative niche. These results reveal the metabolic basis for intracellular bacterial pathogenesis during urinary tract infection and identify subversion of mitochondrial metabolism as a bacterial strategy to facilitate persistence within the urinary tract.
Sensitivity to extracellular potassium underlies type-intrinsic differences in retinal ganglion cell excitability.
Boal AM, McGrady NR, Risner ML, Calkins DJ.
Front Cell Neurosci. 2022 Aug 5;16:966425. doi: 10.3389/fncel.2022.966425. eCollection 2022.
Neuronal type-specific physiologic heterogeneity can be driven by both extrinsic and intrinsic mechanisms. In retinal ganglion cells (RGCs), which carry visual information from the retina to central targets, evidence suggests intrinsic properties shaping action potential (AP) generation significantly impact the responses of RGCs to visual stimuli. Here, we explored how differences in intrinsic excitability further distinguish two RCG types with distinct presynaptic circuits, alpha ON-sustained (αON-S) cells and alpha OFF-sustained (αOFF-S) cells. We found that αOFF-S RGCs are more excitable to modest depolarizing currents than αON-S RGCs but excitability plateaued earlier as depolarization increased (i.e., depolarization block). In addition to differences in depolarization block sensitivity, the two cell types also produced distinct AP shapes with increasing stimulation. αOFF-S AP width and variability increased with depolarization magnitude, which correlated with the onset of depolarization block, while αON-S AP width and variability remained stable. We then tested if differences in depolarization block observed in αON-S and αOFF-S RGCs were due to sensitivity to extracellular potassium. We found αOFF-S RGCs more sensitive to increased extracellular potassium concentration, which shifted αON-S RGC excitability to that of αOFF-S cells under baseline potassium conditions. Finally, we investigated the influence of the axon initial segment (AIS) dimensions on RGC spiking. We found that the relationship between AIS length and evoked spike rate varied not only by cell type, but also by the strength of stimulation, suggesting AIS structure alone cannot fully explain the observed differences RGC excitability. Thus, sensitivity to extracellular potassium contributes to differences in intrinsic excitability, a key factor that shapes how RGCs encode visual information.
Arousal and salience network connectivity alterations in surgical temporal lobe epilepsy.
González HFJ, Narasimhan S, Goodale SE, Johnson GW, Doss DJ, Paulo DL, Morgan VL, Chang C, Englot DJ.
J Neurosurg. 2022 Jul 8:1-11. doi: 10.3171/2022.5.JNS22837. Online ahead of print.
Objective: It is poorly understood why patients with mesial temporal lobe epilepsy (TLE) have cognitive deficits and brain network changes that extend beyond the temporal lobe, including altered extratemporal intrinsic connectivity networks (ICNs). However, subcortical arousal structures project broadly to the neocortex, are affected by TLE, and thus may contribute to these widespread network effects. The authors’ objective was to examine functional connectivity (FC) patterns between subcortical arousal structures and neocortical ICNs, possible neurocognitive relationships, and FC changes after epilepsy surgery.
Methods: The authors obtained resting-state functional magnetic resonance imaging (fMRI) in 50 adults with TLE and 50 controls. They compared nondirected FC (correlation) and directed FC (Granger causality laterality index) within the salience network, default mode network, and central executive network, as well as between subcortical arousal structures; these 3 ICNs were also compared between patients and controls. They also used an fMRI-based vigilance index to relate alertness to arousal center FC. Finally, fMRI was repeated in 29 patients > 12 months after temporal lobe resection.
Results: Nondirected FC within the salience (p = 0.042) and default mode (p = 0.0008) networks, but not the central executive network (p = 0.79), was decreased in patients in comparison with controls (t-tests, corrected). Nondirected FC between the salience network and subcortical arousal structures (nucleus basalis of Meynert, thalamic centromedian nucleus, and brainstem pedunculopontine nucleus) was reduced in patients in comparison with controls (p = 0.0028-0.015, t-tests, corrected), and some of these connectivity abnormalities were associated with lower processing speed index, verbal comprehension, and full-scale IQ. Interestingly, directed connectivity measures suggested a loss of top-down influence from the salience network to the arousal nuclei in patients. After resection, certain FC patterns between the arousal nuclei and salience network moved toward control values in the patients, suggesting that some postoperative recovery may be possible. Although an fMRI-based vigilance measure suggested that patients exhibited reduced alertness over time, FC abnormalities between the salience network and arousal structures were not influenced by the alertness levels during the scans.
Conclusions: FC abnormalities between subcortical arousal structures and ICNs, such as the salience network, may be related to certain neurocognitive deficits in TLE patients. Although TLE patients demonstrated vigilance abnormalities, baseline FC perturbations between the arousal and salience networks are unlikely to be driven solely by alertness level, and some may improve after surgery. Examination of the arousal network and ICN disturbances may improve our understanding of the downstream clinical effects of TLE.
Psychometric validation of a brief self-report measure of misophonia symptoms and functional impairment: The duke-vanderbilt misophonia screening questionnaire.
Williams ZJ, Cascio CJ, Woynaroski TG.
Front Psychol. 2022 Jul 22;13:897901. doi: 10.3389/fpsyg.2022.897901. eCollection 2022.
Misophonia is a newly described disorder of sound tolerance characterized by strong negative emotional reactions to specific “trigger” sounds, resulting in significant distress, pathological avoidance, and impairment in daily life. Research on misophonia is still in its infancy, and most existing psychometric tools for assessing misophonia symptoms have not been extensively validated. The purpose of the current study was to introduce and psychometrically validate the duke-vanderbilt Misophonia Screening Questionnaire (DVMSQ), a novel self-report measure of misophonia symptoms that can be used to determine misophonia “caseness” in clinical and research settings. Employing large online samples of general population adults (n = 1403) and adults on the autism spectrum (n = 936), we rigorously evaluated the internal structure, reliability, validity, and measurement invariance of the DVMSQ. Results indicated that 17 of the 20 original DVMSQ items fit well to a bifactor structure with one “general misophonia” factor and four specific factors (anger/aggression, distress/avoidance, impairment, and global impact). DVMSQ total and subscale scores were highly reliable in both general population and autistic adult samples, and the measure was found to be approximately invariant across age, sex, education level, and autism status. DVMSQ total scores also correlated strongly with another measure of misophonia symptoms (Duke Misophonia Questionnaire-Symptom Scale), with correlations between these two measures being significantly stronger than correlations between the DVMSQ and scales measuring other types of sound intolerance (Inventory of Hyperacusis Symptoms [General Loudness subscale] and DSM-5 Severity Measure for Specific Phobia [modified for phonophobia]). Additionally, DVMSQ items were used to operationalize diagnostic criteria for misophonia derived from the Revised Amsterdam Criteria, which were further updated to reflect a recent consensus definition of misophonia (published after the development of the DVMSQ). Using the new DVMSQ algorithm, 7.3% of general population adults and 35.5% of autistic adults met criteria for clinically significant misophonia. Although additional work is needed to further investigate the psychometric properties of the DVMSQ and validate its theory-based screening algorithm using best-estimate clinical diagnoses, this novel measure represents a potentially useful tool to screen for misophonia and quantify symptom severity and impairment in both autistic adults and the general population.
Dopamine signaling in the nucleus accumbens core mediates latent inhibition.
Kutlu MG, Zachry JE, Melugin PR, Tat J, Cajigas S, Isiktas AU, Patel DD, Siciliano CA, Schoenbaum G, Sharpe MJ, Calipari ES.
Nat Neurosci. 2022 Aug;25(8):1071-1081. doi: 10.1038/s41593-022-01126-1. Epub 2022 Jul 28.
A Randomized Controlled Trial for Audiovisual Multisensory Perception in Autistic Youth.
Feldman JI, Dunham K, DiCarlo GE, Cassidy M, Liu Y, Suzman E, Williams ZJ, Pulliam G, Kaiser S, Wallace MT, Woynaroski TG.
J Autism Dev Disord. 2022 Aug 26. doi: 10.1007/s10803-022-05709-6. Online ahead of print.
Neutrophil-to-Lymphocyte Ratio and Outcomes in Patients Admitted for Acute Heart Failure (As Seen in the BLAST-AHF, Pre-RELAX-AHF, and RELAX-AHF Studies).
Davison BA, Takagi K, Edwards C, Adams KF Jr, Butler J, Collins SP, Dorobantu MI, Ezekowitz JA, Filippatos G, Greenberg BH, Levy PD, Masip J, Metra M, Pang PS, Ponikowski P, Severin TM, Teerlink JR, Teichman SL, Voors AA, Werdan K, Cotter G.
Am J Cardiol. 2022 Aug 3:S0002-9149(22)00708-1. doi: 10.1016/j.amjcard.2022.06.037. Online ahead of print.
Outcomes following surgical resection of cystic intracranial meningiomas.
Tang AR, Chotai S, Grisham CJ, Guidry BS, McDermott JR, Le CH, Morone PJ, Thompson RC, Chambless LB.
J Neurooncol. 2022 Aug 3. doi: 10.1007/s11060-022-04096-3. Online ahead of print.
High fat diet blunts stress-induced hypophagia and activation of Glp1r dorsal lateral septum neurons in male but not in female mice.
Bales MB, Centanni SW, Luchsinger JR, Fathi P, Biddinger JE, Le TDV, Nwaba KG, Paldrmic IM, Winder DG, Ayala JE.
Mol Metab. 2022 Aug 8;64:101571. doi: 10.1016/j.molmet.2022.101571. Online ahead of print.
Podocytes derived from human induced pluripotent stem cells: characterization, comparison, and modeling of diabetic kidney disease.
Bejoy J, Farry JM, Peek JL, Cabatu MC, Williams FM, Welch RC, Qian ES, Woodard LE.
Stem Cell Res Ther. 2022 Jul 26;13(1):355. doi: 10.1186/s13287-022-03040-6.
A Letter to Your Care Providers: Implementation and Analysis of a Letter-based Advance Care Planning Initiative for Gynecologic Oncology Patients.
Zivanov CN, Coogan A, Lane RR, Lin SG, Reed SC, Robinson MA, Karlekar M, Prescott LS, Brown AJ.
J Cancer Educ. 2022 Aug 24:1-8. doi: 10.1007/s13187-022-02214-3. Online ahead of print.