Seth Springer | University of Nebraska Medical Center (original) (raw)

Papers by Seth Springer

Brain Communications

Recent research has indicated that rhythmic visual entrainment may be useful in clearing patholog... more Recent research has indicated that rhythmic visual entrainment may be useful in clearing pathological protein deposits in the central nervous system of mouse models of Alzheimer’s disease. However, visual entrainment studies in human patients with Alzheimer’s disease are rare, and as such the degree to which these patients exhibit aberrations in the neural tracking of rhythmic visual stimuli is unknown. To fill this gap, we recorded magnetoencephalography during a 15 Hz visual entrainment paradigm in amyloid-positive patients on the Alzheimer’s disease spectrum and compared their neural responses to a demographically-matched group of biomarker-negative healthy controls. Magnetoencephalography data were imaged using a beamformer and virtual sensor data were extracted from the peak visual entrainment responses. Our results indicated that, relative to healthy controls, participants on the Alzheimer’s disease spectrum exhibited significantly stronger 15 Hz entrainment in primary visual ...

Psychological Medicine

Background Cannabis is the most widely used illicit drug in the United States and is often associ... more Background Cannabis is the most widely used illicit drug in the United States and is often associated with changes in attention function, which may ultimately impact numerous other cognitive faculties (e.g. memory, executive function). Importantly, despite the increasing rates of cannabis use and widespread legalization in the United States, the neural mechanisms underlying attentional dysfunction in chronic users are poorly understood. Methods We used magnetoencephalography (MEG) and a modified Posner cueing task in 21 regular cannabis users and 32 demographically matched non-user controls. MEG data were imaged in the time−frequency domain using a beamformer and peak voxel time series were extracted to quantify the oscillatory dynamics underlying use-related aberrations in attentional reorienting, as well as the impact on spontaneous neural activity immediately preceding stimulus onset. Results Behavioral performance on the task (e.g. reaction time) was similar between regular cann...

Journal of medicinal chemistry, Jan 23, 2018

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the bl... more The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit diff...

Journal of Medicinal Chemistry, Jul 26, 2018

S5 noted, however, that homology models do not capture the conformational changes between the var... more S5 noted, however, that homology models do not capture the conformational changes between the various states. Future studies with approaches such as molecular dynamics (MD) simulations may help visualize transient states that occur in LAT1. Both the outward-occluded and outward-open models were evaluated for their ability to distinguish between small molecule ligands and likely-non-ligands with docking, by calculating the enrichment of the known ligands with respect to a dataset that included the known ligands and decoys. The ligand set consisted of 1412 compounds, including substrates and inhibitors from the literature, as well as phenylalanine and tyrosine derivatives from our previous study. 6 Eighteen compounds were selected for testing out of 200 from virtual screening against each model. The compound structures are provided on our website (http://www.schlessingerlab.org/data/). 2. Chemistry Experimental TLC plates (silica gel 60, F 254) were purchased from Merck KGaA, Millipore Corporation. Flash Column Chromatography performed using silica gel from Sorbent Technologies in Chemglass columns. Silica Dimensions: porosity 60 Å, particle size: 40-63 µm, 230 x 400 mesh. Preparative HPLC performed on a Gilson PLC 2020. Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 21.2 mm. Preparative HPLC Methods: Each of the following methods employed isocratic elution at 20 mL/min flow rate with the indicated percentage (%) of CH 3 CN in non-buffered Milli-Q deionized water (Integral 5 Water Purification System). A: 0% (i.e. water only); B: 3%; C: 5%; D: 10%. Compounds were dissolved in non-buffered water (unless indicated otherwise) with 10-20% CH 3 CN added as needed for solubility, and filtered through a 0.45 micron syringe filter prior to purification by preparative HPLC. Compounds purified by HPLC were concentrated by lyophilization using a Labconco Freezone 2.5 Plus. Otherwise solutions were concentrated on a Buchi Rotovapor R-210. Analytical HPLC for purity determination was performed on a Waters system (1525 Binary Pump and 2487 Dual λ Absorbance Detector). Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 4.6 mm. Isocratic elution performed with 3% CH 3 CN in 0.1% aq. formic acid at 1.0 mL/min flow rate. Compounds were dissolved in 0.1% aq. formic acid (0.5 mg/mL) for HPLC analysis. LC-MS analysis was performed using an Agilent G6125 single quad ESI source and a 1260 Infinity HPLC system (G7112B Binary Pump and G7114A Dual λ Absorbance Detector). Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 4.6 mm. Unless indicated otherwise, compounds analyzed by LC-MS were dissolved in either 0.03% aq. formic acid (for compounds 63-64, 66-70, 72-84, 86, 98, and 107) or 0.1% aq. TFA (for other compounds and those of Table S2) at 0.2 mg/mL concentration. The following LC-MS methods (A-G) were performed using 1.0 mL/min flow rates: Method A: elution with a ramp of 1% to 5%

Brain Communications

Recent research has indicated that rhythmic visual entrainment may be useful in clearing patholog... more Recent research has indicated that rhythmic visual entrainment may be useful in clearing pathological protein deposits in the central nervous system of mouse models of Alzheimer’s disease. However, visual entrainment studies in human patients with Alzheimer’s disease are rare, and as such the degree to which these patients exhibit aberrations in the neural tracking of rhythmic visual stimuli is unknown. To fill this gap, we recorded magnetoencephalography during a 15 Hz visual entrainment paradigm in amyloid-positive patients on the Alzheimer’s disease spectrum and compared their neural responses to a demographically-matched group of biomarker-negative healthy controls. Magnetoencephalography data were imaged using a beamformer and virtual sensor data were extracted from the peak visual entrainment responses. Our results indicated that, relative to healthy controls, participants on the Alzheimer’s disease spectrum exhibited significantly stronger 15 Hz entrainment in primary visual ...

Psychological Medicine

Background Cannabis is the most widely used illicit drug in the United States and is often associ... more Background Cannabis is the most widely used illicit drug in the United States and is often associated with changes in attention function, which may ultimately impact numerous other cognitive faculties (e.g. memory, executive function). Importantly, despite the increasing rates of cannabis use and widespread legalization in the United States, the neural mechanisms underlying attentional dysfunction in chronic users are poorly understood. Methods We used magnetoencephalography (MEG) and a modified Posner cueing task in 21 regular cannabis users and 32 demographically matched non-user controls. MEG data were imaged in the time−frequency domain using a beamformer and peak voxel time series were extracted to quantify the oscillatory dynamics underlying use-related aberrations in attentional reorienting, as well as the impact on spontaneous neural activity immediately preceding stimulus onset. Results Behavioral performance on the task (e.g. reaction time) was similar between regular cann...

Journal of medicinal chemistry, Jan 23, 2018

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the bl... more The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit diff...

Journal of Medicinal Chemistry, Jul 26, 2018

S5 noted, however, that homology models do not capture the conformational changes between the var... more S5 noted, however, that homology models do not capture the conformational changes between the various states. Future studies with approaches such as molecular dynamics (MD) simulations may help visualize transient states that occur in LAT1. Both the outward-occluded and outward-open models were evaluated for their ability to distinguish between small molecule ligands and likely-non-ligands with docking, by calculating the enrichment of the known ligands with respect to a dataset that included the known ligands and decoys. The ligand set consisted of 1412 compounds, including substrates and inhibitors from the literature, as well as phenylalanine and tyrosine derivatives from our previous study. 6 Eighteen compounds were selected for testing out of 200 from virtual screening against each model. The compound structures are provided on our website (http://www.schlessingerlab.org/data/). 2. Chemistry Experimental TLC plates (silica gel 60, F 254) were purchased from Merck KGaA, Millipore Corporation. Flash Column Chromatography performed using silica gel from Sorbent Technologies in Chemglass columns. Silica Dimensions: porosity 60 Å, particle size: 40-63 µm, 230 x 400 mesh. Preparative HPLC performed on a Gilson PLC 2020. Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 21.2 mm. Preparative HPLC Methods: Each of the following methods employed isocratic elution at 20 mL/min flow rate with the indicated percentage (%) of CH 3 CN in non-buffered Milli-Q deionized water (Integral 5 Water Purification System). A: 0% (i.e. water only); B: 3%; C: 5%; D: 10%. Compounds were dissolved in non-buffered water (unless indicated otherwise) with 10-20% CH 3 CN added as needed for solubility, and filtered through a 0.45 micron syringe filter prior to purification by preparative HPLC. Compounds purified by HPLC were concentrated by lyophilization using a Labconco Freezone 2.5 Plus. Otherwise solutions were concentrated on a Buchi Rotovapor R-210. Analytical HPLC for purity determination was performed on a Waters system (1525 Binary Pump and 2487 Dual λ Absorbance Detector). Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 4.6 mm. Isocratic elution performed with 3% CH 3 CN in 0.1% aq. formic acid at 1.0 mL/min flow rate. Compounds were dissolved in 0.1% aq. formic acid (0.5 mg/mL) for HPLC analysis. LC-MS analysis was performed using an Agilent G6125 single quad ESI source and a 1260 Infinity HPLC system (G7112B Binary Pump and G7114A Dual λ Absorbance Detector). Column: Synergi 4µ Fusion-RP by Phenomenex, 150 x 4.6 mm. Unless indicated otherwise, compounds analyzed by LC-MS were dissolved in either 0.03% aq. formic acid (for compounds 63-64, 66-70, 72-84, 86, 98, and 107) or 0.1% aq. TFA (for other compounds and those of Table S2) at 0.2 mg/mL concentration. The following LC-MS methods (A-G) were performed using 1.0 mL/min flow rates: Method A: elution with a ramp of 1% to 5%