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1.
Neuropharmacology ; 252: 109949, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38636726

ABSTRACT

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.


Subject(s)
Adaptation, Psychological , Aggression , Amphetamines , Hallucinogens , Stress, Psychological , Animals , Male , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Hallucinogens/administration & dosage , Hallucinogens/pharmacology , Adaptation, Psychological/drug effects , Adaptation, Psychological/physiology , Mice , Aggression/drug effects , Aggression/physiology , Amphetamines/pharmacology , Amphetamines/administration & dosage , Mice, Inbred C57BL , Tumor Necrosis Factor-alpha/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Agonists/administration & dosage , Escape Reaction/drug effects , Coping Skills
2.
Chem Commun (Camb) ; 60(32): 4346-4349, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38545873

ABSTRACT

We present soft-template encapsulation of salt hydrate phase change materials (PCMs) using modified silica particles to both stabilize emulsions and serve as initiators for organocatalyzed photoredox ATRP. The resulting core-shell structures have high core loading and are robust to thermal cycling. Critically, this strategy eliminates the need for a reagent in the core phase, thus preserving purity, and offers the ability to tailor shell composition for desired applications.

3.
Curr Sports Med Rep ; 22(9): 307-312, 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37678349

ABSTRACT

ABSTRACT: Frozen shoulder is a common condition that causes pain and restriction of movement of the shoulder unrelated to secondary causes. It has three classic phases (freezing, frozen, and thawing), and is resolved in most cases within 1 to 2 years. Diagnosis is clinical based on global motion restriction and pain. Imaging plays an ancillary role to narrow the differential diagnosis. Physical therapy, nonsteroidal anti-inflammatories, and injection therapies are standard treatments, although none have been shown to alter the long-term course of the condition. Ultrasound guidance is recommended for injection-based therapy, although not required. Further study should focus on long-term outcomes and treatments that significantly alter the natural course of the disease.


Subject(s)
Bursitis , Humans , Diagnosis, Differential , Bursitis/diagnosis , Bursitis/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Movement , Pain
4.
eNeuro ; 10(4)2023 04.
Article in English | MEDLINE | ID: mdl-37011954

ABSTRACT

A rapidly approaching dark object evokes an evolutionarily conserved fear response in both vertebrates and invertebrates, young to old. A looming visual stimulus mimics an approaching object and triggers a similarly robust fear response in mice, resulting in freeze and flight. However, the retinal neural pathway responsible for this innate response has not been fully understood. We first explored a variety of visual stimuli that reliably induced these innate responses, and found that a looming stimulus with 2-d acclimation consistently evoked fear responses. Because the fear responses were triggered by the looming stimulus with moving edges, but not by a screen flipping from light to dark, we targeted the starburst amacrine cells (SACs), crucial neurons for retinal motion detection. We used intraocular injection of diphtheria toxin (DT) in mutant mice expressing diphtheria toxin receptors (DTR) in SACs. The looming-evoked fear responses disappeared in half of the DT-injected mice, and the other mice still exhibited the fear responses. The optomotor responses (OMRs) were reduced or eliminated, which occurred independent of the disappearance of the fear responses. A histologic examination revealed that ON SACs were reduced in both mouse groups preserved or absent fear responses. In contrast, the number of OFF SACs was different among two groups. The OFF SACs were relatively preserved in mice exhibiting continued fear responses, whereas they were ablated in mice lacking fear response to looming stimulation. These results indicate that OFF SACs and the direction-selective pathway in the retina play a role in looming-induced fear behaviors.


Subject(s)
Amacrine Cells , Retina , Mice , Animals , Amacrine Cells/metabolism , Retina/metabolism , Neural Pathways
5.
Article in English | MEDLINE | ID: mdl-38444728

ABSTRACT

The retina is comprised of diverse neural networks, signaling from photoreceptors to ganglion cells to encode images. The synaptic connections between these retinal neurons are crucial points for information transfer; however, the input-output relations of many synapses are understudied. Starburst amacrine cells in the retina are known to contribute to retinal motion detection circuits, providing a unique window for understanding neural computations. We examined the dual transmitter release of GABA and acetylcholine from starburst amacrine cells by optogenetic activation of these cells, and conducted patch clamp recordings from postsynaptic ganglion cells to record excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs). As starburst amacrine cells exhibit distinct kinetics in response to objects moving in a preferred or null direction, we mimicked their depolarization kinetics using optogenetic stimuli by varying slopes of the rising phase. The amplitudes of EPSCs and IPSCs in postsynaptic ganglion cells were reduced as the stimulus rising speed was prolonged. However, the sensitivity of postsynaptic currents to the stimulus slope differed. EPSC amplitudes were consistently reduced as the steepness of the rising phase fell. By contrast, IPSCs were less sensitive to the slope of the stimulus rise phase and maintained their amplitudes until the slope became shallow. These results indicate that distinct synaptic release mechanisms contribute to acetylcholine and GABA release from starburst amacrine cells, which could contribute to the ganglion cells' direction selectivity.

6.
STAR Protoc ; 3(3): 101482, 2022 09 16.
Article in English | MEDLINE | ID: mdl-35769922

ABSTRACT

Bipolar cells are the second-order neurons in the retina that are less accessible for investigating their synaptic responses. Here, we present a protocol to conduct patch clamp recordings from bipolar cells in the wholemount retina from Ai32 mutant mice. We detail whole-cell patch-clamp recording from bipolar cells to examine their light-evoked responses to optogenetic stimulation, followed by imaging terminals of recorded cells to determine bipolar cell type. We describe light stimulus information to activate channelrhodopsin-2 (ChR2). For complete details on the use and execution of this protocol, please refer to Hellmer et al. (2021).


Subject(s)
Neurons , Retina , Animals , Mice , Optogenetics , Patch-Clamp Techniques , Retina/physiology
7.
J Environ Manage ; 313: 115004, 2022 Jul 01.
Article in English | MEDLINE | ID: mdl-35405544

ABSTRACT

Stormwater management problems are expanding as urbanization continues and precipitation patterns are increasingly extreme. Urban soils are often more disturbed and compacted than non-urban soils, therefore, rainfall run-off estimates based on models designed for non-urban soils may not be accurate due to altered soil infiltration rates. Our objective was to quantify soil infiltration rates across an urban watershed and compare them to estimates from rainfall-runoff models commonly used in stormwater management (Horton and Green-Ampt) as well as an alternate, random-forest model created using available geospatial data. We measured infiltration rates and collected data on soil properties (texture, bulk density) and context (land use, ground cover, time since development) at 89 points across the 102 ha Walnut Creek watershed in Raleigh, North Carolina (USA). Forest land covers and forest ground covers (leaf litter) had the highest infiltration capacities; however, all of our measurements indicate that urban soils in the Walnut Creek watershed are able to absorb most precipitation events and are likely capable of infiltrating additional urban stormwater runoff. Comparisons between observations and the rainfall-runoff model estimates reveal that both underestimated urban soil infiltration rates. Despite higher than expected urban soil infiltration capacity, stormwater management remains a challenge in this urban watershed. Therefore, to reduce stormwater runoff from impervious surfaces through soil infiltration, impervious surfaces should be disconnected, especially adjacent to new development, and urban forests should be conserved. Further, because our random forest model more accurately captured watershed infiltration rates than the rainfall-runoff models, we propose this type of machine learning approach as an alternative method for informing stormwater management and prioritizing areas for impervious disconnection.


Subject(s)
Rain , Soil , North Carolina , Urbanization , Water Movements
8.
Med Sci Educ ; 32(1): 91-102, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35154895

ABSTRACT

PROBLEM: At present, formal training in adult learning principles, educational theories, and educational methods is not a core objective of most medical school curricula. As academic medical centers aim to develop the next generation of medical educators, students must be provided an opportunity to learn educational principles, engage in supervised teaching activities, and develop experiences in academic medicine to foster interest early in their development as educators. INTERVENTION: We developed a longitudinal medical education elective for fourth-year medical students, which was comprised of attending five seminars, leading 15 teaching sessions, formulating a medical education project, and writing a reflective essay. The seminars covered the history of medical education in the USA, adult learning theory and teaching principles, use of various teaching strategies and formats, construction and organization of curricula, effective models of evaluation and feedback provision, and principles of educational research. CONTEXT: This exploratory quasi-experiment incorporated a concurrent mixed methods data collection approach via pre- and post-seminar surveys and narrative reflection essay document analyses. IMPACT: Learners revealed favorable changes in their self-efficacy and self-perceived knowledge and attitudes towards medical education. A qualitative analysis of the reflective essays revealed five thematic categories (learning impacts, medical educator growth, leadership growth, medical school reflections, and future professional plans) and thirteen sub-categories. Students found many opportunities to implement high-quality educational projects, expressed commitment to pursuing teaching careers, and felt better equipped to assume a leadership role as change agents in academic medicine. LESSONS LEARNED: Findings are likely relevant to critical stakeholders who advocate for the inclusion of formal educational skills training into medical education curricula.

9.
Cell Rep ; 37(11): 110106, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34910920

ABSTRACT

Retinal bipolar cells are second-order neurons that transmit basic features of the visual scene to postsynaptic partners. However, their contribution to motion detection has not been fully appreciated. Here, we demonstrate that cholinergic feedback from starburst amacrine cells (SACs) to certain presynaptic bipolar cells via alpha-7 nicotinic acetylcholine receptors (α7-nAChRs) promotes direction-selective signaling. Patch clamp recordings reveal that distinct bipolar cell types making synapses at proximal SAC dendrites also express α7-nAChRs, producing directionally skewed excitatory inputs. Asymmetric SAC excitation contributes to motion detection in On-Off direction-selective ganglion cells (On-Off DSGCs), predicted by computational modeling of SAC dendrites and supported by patch clamp recordings from On-Off DSGCs when bipolar cell α7-nAChRs is eliminated pharmacologically or by conditional knockout. Altogether, these results show that cholinergic feedback to bipolar cells enhances direction-selective signaling in postsynaptic SACs and DSGCs, illustrating how bipolar cells provide a scaffold for postsynaptic microcircuits to cooperatively enhance retinal motion detection.


Subject(s)
Action Potentials , Cell Movement , Cholinergic Agents/metabolism , Retinal Bipolar Cells/physiology , Synapses/physiology , Synaptic Transmission , alpha7 Nicotinic Acetylcholine Receptor/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Retinal Ganglion Cells/physiology , Visual Pathways
10.
Mol Syst Des Eng ; 6(12): 1003-1015, 2021 Dec 01.
Article in English | MEDLINE | ID: mdl-35096418

ABSTRACT

Inspired by Nature's tunability driven by the modulation of structural organization, we utilize peptide motifs as an approach to tailor not only hierarchical structure, but also thermo-responsive shape memory properties of conventional polymeric materials. Specifically, poly(ß-benzyl-L-aspartate)-b-poly(dimethylsiloxane)-b-poly(ß-benzyl-L-aspartate) was incorporated as the soft segment in peptide-polyurea hybrids to manipulate hierarchical ordering through peptide secondary structure and a balance of inter- and intra-molecular hydrogen bonding. Employing these bioinspired peptidic polyureas, we investigated the influence of secondary structure on microphase-separated morphology, and shape fixity and recovery via attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), small-angle X-ray scattering (SAXS) and dynamic mechanical analysis (DMA). The ß-sheet motifs promoted phase mixing through extensive inter-molecular hydrogen bonding between the hard block and peptide segments and provided an increased chain elasticity, resulting in decreased shape fixity compared to a non-peptidic control. In contrast, intra-molecular hydrogen bonding driven by the α-helical arrangements yielded a microphase-separated and hierarchically ordered morphology, leading to an increase in the shape fixing ratio. These results indicate that peptide secondary structure provides a convenient handle for tuning shape memory properties by regulating hydrogen bonding with the surrounding polyurea hard segment, wherein extent of hydrogen bonding and phase mixing between the peptidic block and hard segment dictate the resulting shape memory behaviour. Furthermore, the ability to shift secondary structure as a function of temperature was also demonstrated as a pathway to influence shape memory response. This research highlights that peptide secondary conformation influences the hierarchical ordering and modulates the shape memory response of peptide-polymer hybrids. We anticipate that these findings will enable the design of smart bio-inspired materials with responsive and tailored function via a balance of hydrogen bonding character, structural organization, and mechanics.

11.
Front Cell Neurosci ; 14: 253, 2020.
Article in English | MEDLINE | ID: mdl-32922266

ABSTRACT

The retina and the olfactory bulb are the gateways to the visual and olfactory systems, respectively, similarly using neural networks to initiate sensory signal processing. Sensory receptors receive signals that are transmitted to neural networks before projecting to primary cortices. These networks filter sensory signals based on their unique features and adjust their sensitivities by gain control systems. Interestingly, dopamine modulates sensory signal transduction in both systems. In the retina, dopamine adjusts the retinal network for daylight conditions ("light adaptation"). In the olfactory system, dopamine mediates lateral inhibition between the glomeruli, resulting in odorant signal decorrelation and discrimination. While dopamine is essential for signal discrimination in the olfactory system, it is not understood whether dopamine has similar roles in visual signal processing in the retina. To elucidate dopaminergic effects on visual processing, we conducted patch-clamp recording from second-order retinal bipolar cells, which exhibit multiple types that can convey different temporal features of light. We recorded excitatory postsynaptic potentials (EPSPs) evoked by various frequencies of sinusoidal light in the absence and presence of a dopamine receptor 1 (D1R) agonist or antagonist. Application of a D1R agonist, SKF-38393, shifted the peak temporal responses toward higher frequencies in a subset of bipolar cells. In contrast, a D1R antagonist, SCH-23390, reversed the effects of SKF on these types of bipolar cells. To examine the mechanism of dopaminergic modulation, we recorded voltage-gated currents, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and low-voltage activated (LVA) Ca2+ channels. SKF modulated HCN and LVA currents, suggesting that these channels are the target of D1R signaling to modulate visual signaling in these bipolar cells. Taken together, we found that dopamine modulates the temporal tuning of a subset of retinal bipolar cells. Consequently, we determined that dopamine plays a role in visual signal processing, which is similar to its role in signal decorrelation in the olfactory bulb.

12.
Hosp Pediatr ; 10(7): 600-607, 2020 07.
Article in English | MEDLINE | ID: mdl-32591440

ABSTRACT

OBJECTIVES: Nearly one-quarter of individuals diagnosed with avoidant/restrictive food intake disorder (ARFID) require medical admission. There have been efforts to characterize ARFID in outpatient and intensive day treatment settings; however, authors of few studies have examined this presentation in the inpatient pediatric hospital setting. In this study, we aim to further characterize patients presenting to the hospital with concerns for ARFID. METHODS: This study involved a retrospective chart review of medically admitted patients with ARFID seen by the psychiatry consultation service at a tertiary care New England pediatric hospital from 2015 to 2016. RESULTS: The typical hospitalized patient with ARFID was a 12.9-year-old, white girl with previous history of outpatient mental health treatment, anxiety disorder, and gastrointestinal-related diagnoses admitted to adolescent medicine or pediatric hospitalist services with >1 year of feeding difficulties often triggered by a precipitating event. Despite >80% of subjects receiving evaluations as outpatients for feeding-related concerns, including 60.5% seeing their primary care provider, <20% were diagnosed with ARFID before hospitalization. The average length of admission was 8 days. All imaging, scopes, and swallow studies conducted during the admission were nonrevealing. Almost half of patients required enteral tube feeds, and 63.2% required psychiatric medications during the admission. Only 31.6% of patients had the ARFID diagnosis documented in their discharge notes. CONCLUSIONS: Consistent identification of ARFID remains variable, underrecognized by community providers, and underdocumented by hospital providers. Accurate recognition of ARFID and additional study into contributory factors and treatment approaches may help improve effective health care use and treatment outcomes.


Subject(s)
Avoidant Restrictive Food Intake Disorder , Feeding and Eating Disorders , Adolescent , Child , Eating , Feeding and Eating Disorders/diagnosis , Feeding and Eating Disorders/therapy , Female , Hospitals, Pediatric , Humans , Retrospective Studies
13.
ACS Macro Lett ; 9(9): 1198-1216, 2020 Sep 15.
Article in English | MEDLINE | ID: mdl-35638621

ABSTRACT

Supramolecular polymers allow access to dynamic materials, where noncovalent interactions can be used to offer both enhanced material toughness and stimuli-responsiveness. The versatility of self-assembly has enabled these supramolecular motifs to be incorporated into a wide array of glassy and elastomeric materials; moreover, the interaction of these noncovalent motifs with their environment has shown to be a convenient platform for controlling material properties. In this Viewpoint, supramolecular polymers are examined through their self-assembly chemistries, approaches that can be used to control their self-assembly (e.g., covalent cross-links, nanofillers, etc.), and how the strategic application of supramolecular polymers can be used as a platform for designing the next generation of smart materials. This Viewpoint provides an overview of the aspects that have garnered interest in supramolecular polymer chemistry, while also highlighting challenges faced and innovations developed by researchers in the field.

14.
Orthop Traumatol Surg Res ; 106(1): 61-66, 2020 02.
Article in English | MEDLINE | ID: mdl-31883868

ABSTRACT

INTRODUCTION: Sleep dysfunction in patients with rotator cuff tears has been previously evaluated only using subjective measures. Objective parameters of sleep quality amongst rotator cuff tear patients are scarce in the literature. The aim of this study is to compare objective sleep data to historical controls and to subjective patient-reported sleep quality in patients with rotator cuff tears. HYPOTHESIS: We hypothesized that patients with rotator cuff tears would demonstrate objectively poor sleep quality based on actigraphy when compared to a historical control group. Secondarily, we hypothesize that objective sleep quality measures will correlate poorly with traditionally used questionnaires and other subjective assessments. MATERIALS AND METHODS: Twenty patients with full-thickness rotator cuff tears wore a highly validated activity monitor for 2 consecutive weeks for objective assessment and completed a sleep diary during the same period. Patients completed multiple questionnaires pertaining to their shoulder function and subjective assessment of sleep quality. Objective sleep assessments were compared to patients' sleep diary data and to subjective sleep data from a historical cohort of 969 healthy adults aged 57-97 years. RESULTS: Mean total sleep time, sleep onset latency, wake after sleep onset (WASO), and sleep efficiency were all significantly worse in the study cohort compared to the historical cohort (p=0.0338, p=0.0040, p<0.0001, and p=0.0474, respectively). Pittsburgh Sleep Quality Index (PSQI) scores did not correlate with sleep efficiency (r=0.3143, p=0.2040) or WASO (r=-0.3068, p=0.2153). Visual analog scale scores correlated with PSQI scores (r=0.5260, p=0.0249) and Epworth Sleepiness Scale scores (r=0.4863, p=0.0407). Patients tended to overreport their time spent asleep via a sleep diary compared to objective time asleep (p=0.0050). DISCUSSION: This study of objective sleep measures demonstrated poor sleep quality in patients with rotator cuff tears with shorter sleep duration, frequent awakenings, and decreased efficiency. Subjective assessments of sleep did not correlate with objective findings. LEVEL OF EVIDENCE: Level II, prospective cohort study.


Subject(s)
Rotator Cuff Injuries , Sleep , Aged , Aged, 80 and over , Case-Control Studies , Humans , Middle Aged , Pain Measurement , Prospective Studies , Rotator Cuff , Rotator Cuff Injuries/complications , Treatment Outcome
15.
J Vis Exp ; (148)2019 06 13.
Article in English | MEDLINE | ID: mdl-31259889

ABSTRACT

The visual system in the central nervous system processes diverse visual signals. Although the overall structure has been characterized from the retina through the lateral geniculate nucleus to the visual cortex, the system is complex. Cellular and molecular studies have been conducted to elucidate the mechanisms underpinning visual processing and, by extension, disease mechanisms. These studies may contribute to the development of artificial visual systems. To validate the results of these studies, behavioral vision testing is necessary. Here, we show that the looming stimulation experiment is a reliable mouse vision test that requires a relatively simple setup. The looming experiment was conducted in a large enclosure with a shelter in one corner and a computer monitor located on the ceiling. A CCD camera positioned next to the computer monitor served to observe mouse behavior. A mouse was placed in the enclosure for 10 minutes and allowed to acclimate to and explore the surroundings. Then, the monitor projected a program-derived looming stimulus 10 times. The mouse responded to the stimuli either by freezing or by fleeing to the hiding place. The mouse's behavior before and after the looming stimuli was recorded, and the video was analyzed using motion tracking software. The velocity of the mouse movement significantly changed after the looming stimuli. In contrast, no reaction was observed in blind mice. Our results demonstrate that the simple looming experiment is a reliable test of mouse vision.


Subject(s)
Vision, Ocular/physiology , Visual Perception/physiology , Animals , Male , Mice
16.
Invest Ophthalmol Vis Sci ; 60(5): 1353-1361, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30934054

ABSTRACT

Purpose: Motion detection is performed by a unique neural network in the mouse retina. Starburst amacrine cells (SACs), which release acetylcholine and gamma-aminobutyric acid (GABA) into the network, are key neurons in the motion detection pathway. Although GABA contributions to the network have been extensively studied, the role of acetylcholine is minimally understood. Acetylcholine receptors are present in a subset of bipolar, amacrine, and ganglion cells. We focused on α7-nicotinic acetylcholine receptor (α7-nAChR) expression in bipolar cells, and investigated which types of bipolar cells possess α7-nAChRs. Methods: Retinal slice sections were prepared from C57BL/6J and Gus8.4-GFP mice. Specific expression of α7-nAChRs in bipolar cells was examined using α-bungarotoxin (αBgTx)-conjugated Alexa dyes co-labeled with specific bipolar cell markers. Whole-cell recordings were conducted from bipolar cells in retinal slice sections. A selective α7-nAChR agonist, PNU282987, was applied by a puff and responses were recorded. Results: αBgTx fluorescence was observed primarily in bipolar cell somas. We found that α7-nAChRs were expressed by the majority of type 1, 2, 4, and 7 bipolar cells. Whole-cell recordings revealed that type 2 and 7 bipolar cells depolarized by PNU application. In contrast, α7-nAChRs were not detected in most of type 3, 5, 6, and rod bipolar cells. Conclusions: We found that α7-nAChRs are present in bipolar cells in a type-specific manner. Because these bipolar cells provide synaptic inputs to SACs and direction selective ganglion cells, α7-nAChRs may play a role in direction selectivity by modulating these bipolar cells' outputs.


Subject(s)
Retinal Bipolar Cells/metabolism , Synaptic Transmission/physiology , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Benzamides/pharmacology , Bridged Bicyclo Compounds/pharmacology , Mice , Mice, Inbred C57BL , Models, Animal , Motion Perception/physiology , Nicotinic Agonists/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors
17.
Physiol Rep ; 6(20): e13885, 2018 10.
Article in English | MEDLINE | ID: mdl-30338673

ABSTRACT

The canonical mGluR6-Trpm1 pathway that generates the sign-inverting signal between photoreceptors and ON bipolar cells has been well described. However, one type of ON bipolar cell, the rod bipolar cell (RBC), additionally is thought to express the group I mGluRs whose function is unknown. We examined the role of group I mGluRs in mouse RBCs and here provide evidence that it controls synaptic gain between rods and RBCs. In dark-adapted conditions, the mGluR1 antagonists LY367385 and (RS)-1-Aminoindan-1,5-dicarboxylic acid, but not the mGluR5 antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride reduced the light-evoked responses in RBCs indicating that mGluR1, but not mGluR5, serves to potentiate RBC responses. Perturbing the downstream phospholipase C (PLC)-protein kinase C (PKC) pathway by inhibiting PLC, tightly buffering intracellular Ca2+ , or preventing its release from intracellular stores reduced the synaptic potentiation by mGluR1. The effect of mGluR1 activation was dependent upon adaptation state, strongly increasing the synaptic gain in dark-, but not in light-adapted retinas, or in the presence of a moderate background light, consistent with the idea that mGluR1 activation requires light-dependent glutamate release from rods. Moreover, immunostaining revealed that protein kinase Cα (PKCα) is more strongly expressed in RBC dendrites in dark-adapted conditions, revealing an additional mechanism behind the loss of mGluR1 potentiation. In light-adapted conditions, exogenous activation of mGluR1 with the agonist 3,5-Dihydroxyphenylglycine increased the mGluR6 currents in some RBCs and decreased it in others, suggesting an additional action of mGluR1 that is unmasked in the light-adapted state. Elevating intracellular free Ca2+ , consistently resulted in a decrease in synaptic gain. Our results provide evidence that mGluR1 controls the synaptic gain in RBCs.


Subject(s)
Receptors, Metabotropic Glutamate/metabolism , Retinal Bipolar Cells/metabolism , Retinal Rod Photoreceptor Cells/metabolism , Synaptic Potentials , Animals , Calcium/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Protein Kinase C/metabolism , Receptor, Metabotropic Glutamate 5/agonists , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Receptor, Metabotropic Glutamate 5/metabolism , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Retinal Bipolar Cells/physiology , Retinal Rod Photoreceptor Cells/physiology , Type C Phospholipases/metabolism
18.
Biomacromolecules ; 19(8): 3445-3455, 2018 08 13.
Article in English | MEDLINE | ID: mdl-30001123

ABSTRACT

Peptide-polymer hybrids combine the hierarchy of biological species with synthetic concepts to achieve control over molecular design and material properties. By further incorporating covalent cross-links, the enhancement of molecular complexity is achieved, allowing for both a physical and covalent network. In this work, the structure and function of poly(ethylene glycol) (PEG)-network hybrids are tuned by varying peptide block length and overall peptide content. Here the impact of poly(ε-carbobenzyloxy-l-lysine) (PZLY) units on block interactions and mechanics is explored by probing secondary structure, PEG crystallinity, and hierarchical organization. The incorporation of PZLY reveals a mixture of α-helices and ß-sheets at smaller repeat lengths ( n = 5) and selective α-helix formation at a higher peptide molecular weight ( n = 20). Secondary structure variations tailored the solid-state film hierarchy, whereby nanoscale fibers and microscale spherulites varied in size depending on the amount of α-helices and ß-sheets. This long-range ordering influenced mechanical properties, resulting in a decrease in elongation-at-break (from 400 to 20%) with increasing spherulite diameter. Furthermore, the reduction in soft segment crystallinity with the addition of PZLY resulted in a decrease in moduli. It was determined that, by controlling PZLY content, a balance of physical associations and self-assembly is obtained, leading to tunable PEG crystallinity, spherulite formation, and mechanics.


Subject(s)
Polylysine/analogs & derivatives , Polymers/chemistry , Crystallization , Mechanical Phenomena , Polyethylene Glycols/chemistry , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand
19.
Am J Obstet Gynecol ; 219(2): 174.e1-174.e8, 2018 08.
Article in English | MEDLINE | ID: mdl-29792853

ABSTRACT

BACKGROUND: Women with a gynecologic cancer tend to be older, obese, and postmenopausal, characteristics that are associated with an increased risk for obstructive sleep apnea. However, there is limited investigation regarding the condition's prevalence in this population or its impact on postoperative outcomes. In other surgical populations, patients with obstructive sleep apnea have been observed to be at increased risk for adverse postoperative events. OBJECTIVE: We sought to estimate the prevalence of obstructive sleep apnea among gynecologic oncology patients undergoing elective surgery and to investigate for a relationship between obstructive sleep apnea and postoperative outcomes. STUDY DESIGN: Patients referred to an academic gynecologic oncology practice were approached for enrollment in this prospective, observational study. Patients were considered eligible for study enrollment if they were scheduled for a nonemergent inpatient surgery and could provide informed consent. Enrolled patients were evaluated for a preexisting diagnosis of obstructive sleep apnea. Those without a prior diagnosis were screened using the validated, 4-item STOP questionnaire (ie, Snore loudly, daytime Tiredness, Observed apnea, elevated blood Pressure). All patients who screened positive for obstructive sleep apnea were referred for polysomnography. The primary outcome was the prevalence of women with obstructive sleep apnea or those who screened at high risk for the condition. Secondary outcomes examined the correlation between body mass index (kg/m2) with obstructive sleep apnea and assessed for a relationship between obstructive sleep apnea and postoperative outcomes. RESULTS: Over a 22-month accrual period, 383 eligible patients were consecutively approached to participate in the study. A cohort of 260 patients were enrolled. A total of 33/260 patients (13%) were identified as having a previous diagnosis of obstructive sleep apnea. An additional 66/260 (25%) screened at risk for the condition using the STOP questionnaire. Of the patients who screened positive, 8/66 (12%) completed polysomnography, all of whom (8/8 [100%]) were found to have obstructive sleep apnea. The prevalence of previously diagnosed obstructive sleep apnea or screening at risk for the condition increased as body mass index increased (P < .001). Women with untreated obstructive sleep apnea and those who screened at risk for the condition were found to have an increased risk for postoperative hypoxemia (odds ratio, 3.5; 95% confidence interval, 1.8-4.7; P = .011) and delayed return of bowel function (odds ratio, 2.1; 95% confidence interval, 1.3-4.5; P = .009). CONCLUSION: The prevalence of obstructive sleep apnea or screening at risk for the condition is high among women presenting for surgery with a gynecologic oncologist. Providers should consider evaluating a patient's risk for obstructive sleep apnea in the preoperative setting, especially when risk factors for the condition are present.


Subject(s)
Genital Neoplasms, Female/surgery , Hypoxia/epidemiology , Postoperative Complications/epidemiology , Sleep Apnea, Obstructive/epidemiology , Adult , Aged , Aged, 80 and over , Body Mass Index , Female , Genital Neoplasms, Female/epidemiology , Gynecologic Surgical Procedures , Humans , Hypertension , Longitudinal Studies , Mass Screening , Middle Aged , Odds Ratio , Polysomnography , Preoperative Care/methods , Prevalence , Prospective Studies , Sleep Apnea, Obstructive/diagnosis , Sleepiness , Snoring , Young Adult
20.
Methods Mol Biol ; 1753: 217-233, 2018.
Article in English | MEDLINE | ID: mdl-29564792

ABSTRACT

Retinal first-order neurons, photoreceptors, receive visual inputs and convert them to neural signals. The second-order neurons, bipolar cells then sort out the visual signals and encode them through multiple neural streams. Approximately 15 morphological types of bipolar cells have been identified, which are thought to encode different aspects of visual signals such as motion and color (Ichinose et al. J Neurosci 34(26):8761-8771, 2014; Euler et al. Nat Rev Neurosci 15(8):507-519, 2014). To investigate functional aspects of OFF bipolar cells, single cell recordings are preferred; however, bipolar cells in the mouse retina are small and hard to distinguish from other types of cells. Here, we describe our methodology and tips for immunohistochemistry and patch clamp recordings for analyzing light-evoked responses in each type of OFF bipolar cell.


Subject(s)
Patch-Clamp Techniques/methods , Photic Stimulation/methods , Retinal Bipolar Cells/physiology , Animals , Biotin/analogs & derivatives , Biotin/pharmacology , Immunohistochemistry/instrumentation , Immunohistochemistry/methods , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Microscopy, Confocal/instrumentation , Microscopy, Confocal/methods , Patch-Clamp Techniques/instrumentation , Photic Stimulation/instrumentation , Retinal Bipolar Cells/drug effects
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