Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13394
Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts
BACKGROUND:Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling, including fibroblast proliferation, contribute to changes in Ca2+ handling which promote the appearance of Ca2+ alternans (Ca-alt). Ca-alt in turn give rise to repolarization alternans, which promote dispersion of repolarization and contribute to reentrant activity. The computational analysis of the incidence of Ca2+ and/or repolarization alternans under HF conditions in the presence of fibroblasts could provide a better understanding of the mechanisms leading to HF arrhythmias and contractile function disorders. METHODS AND FINDINGS/RESULTS:The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions. CONCLUSION/CONCLUSIONS:It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart.
PMID: 31211790
ISSN: 1932-6203
CID: 3939102
Large-scale brain functional network topology disruptions underlie symptom heterogeneity in children with attention-deficit/hyperactivity disorder
Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.
PMID: 30472167
ISSN: 2213-1582
CID: 3500972
Effect of hydroxycitrate (HCA) on urinary risk factors for calcium-based kidney stones [Meeting Abstract]
Background: Potassium citrate is a mainstay of treatment to prevent calcium stones. However, it can increase urine pH and calcium phosphate (CaP) supersaturation (SS). HCA, extracted from garcinia cambogia, is a potent inhibitor of calcium oxalate (CaOx) crystal growth in vitro and may not yield HCO3 . It is "generally regarded as safe" and available over the counter. We studied how HCA supplementation affects urine chemistry.
Method(s): We enrolled 2 groups: calcium stone formers (SF) and non-stone forming (NSF) controls. Thiazides and potassium citrate were held for 2 weeks prior to study. Participants recorded a self-selected diet for 2 days and performed 24-hour urine collection on day 2. HCA 300 mg 3 times daily was taken orally for 7 days, and 24-hour urine collected on day 7 while the patient replicated the initial, self-selected diet.
Result(s): 13 people, aged 26-76 years, participated. There were 6 SF and 7 NSF, combined into 1 group of 13. Patients replicated their diets well, as urine Na, volume, and creatinine were similar (data not shown). Results presented in Table. HCA increased urine K and citrate (P < 0.001 and 0.013 respectively). Mean urine pH was unchanged (6.25 to 6.47, P=0.14), while urinary NH4 fell (P = 0.017). 24h excretion of Ca and Ox did not change. SS of CaOx and CaP did not change. Serum values did not change: baseline HCO3 and K were 23.5 +/- 2.5 and 4.0 +/- 0.2 meq/L and 23.7 +/- 1.8 and 4.4 +/- 0.6 meq/L after HCA.
Conclusion(s): Urine K excretion rose by 29 meq/day compared with an expected increase based on the label of 14 meq, suggesting the label was not accurate. Increased citrate and lower NH4 suggest some K is in the form of alkali salts or that some HCA is metabolized to bicarbonate. There was no change in CaP or CaOx SS. The lack of effect on SS may not reflect the potential ability of HCA to inhibit calcium crystallization, as it inhibits Ca crystal growth in vitro in supersaturated media
Method(s): We enrolled 2 groups: calcium stone formers (SF) and non-stone forming (NSF) controls. Thiazides and potassium citrate were held for 2 weeks prior to study. Participants recorded a self-selected diet for 2 days and performed 24-hour urine collection on day 2. HCA 300 mg 3 times daily was taken orally for 7 days, and 24-hour urine collected on day 7 while the patient replicated the initial, self-selected diet.
Result(s): 13 people, aged 26-76 years, participated. There were 6 SF and 7 NSF, combined into 1 group of 13. Patients replicated their diets well, as urine Na, volume, and creatinine were similar (data not shown). Results presented in Table. HCA increased urine K and citrate (P < 0.001 and 0.013 respectively). Mean urine pH was unchanged (6.25 to 6.47, P=0.14), while urinary NH4 fell (P = 0.017). 24h excretion of Ca and Ox did not change. SS of CaOx and CaP did not change. Serum values did not change: baseline HCO
Conclusion(s): Urine K excretion rose by 29 meq/day compared with an expected increase based on the label of 14 meq, suggesting the label was not accurate. Increased citrate and lower NH4 suggest some K is in the form of alkali salts or that some HCA is metabolized to bicarbonate. There was no change in CaP or CaOx SS. The lack of effect on SS may not reflect the potential ability of HCA to inhibit calcium crystallization, as it inhibits Ca crystal growth in vitro in supersaturated media
EMBASE:633767928
ISSN: 1533-3450
CID: 4755112
Affibody-Mediated Sequestration of Amyloid β Demonstrates Preventive Efficacy in a Transgenic Alzheimer's Disease Mouse Model
Different strategies for treatment and prevention of Alzheimer's disease (AD) are currently under investigation, including passive immunization with anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of Aβ-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted ZSYM73-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric ZSYM73 affibody for sequestering of monomeric Aβ-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with ZSYM73-ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric Aβ, demonstrating a therapeutic potential for prevention of AD.
PMCID:6440316
PMID: 30967771
ISSN: 1663-4365
CID: 3797022
Algorithms And Circuits For Olfactory Navigation In Drosophila [Meeting Abstract]
ISI:000493389500058
ISSN: 0379-864x
CID: 4221922
Compound stimuli reveal the structure of visual motion selectivity in macaque MT neurons
Motion selectivity in primary visual cortex (V1) is approximately separable in orientation, spatial frequency, and temporal frequency ("frequency-separable"). Models for area MT neurons posit that their selectivity arises by combining direction-selective V1 afferents whose tuning is organized around a tilted plane in the frequency domain, specifying a particular direction and speed ("velocity-separable"). This construction explains "pattern direction selective" MT neurons, which are velocity-selective but relatively invariant to spatial structure, including spatial frequency, texture and shape. We designed a set of experiments to distinguish frequency- and velocity-separable models and executed them with single-unit recordings in macaque V1 and MT. Surprisingly, when tested with single drifting gratings, most MT neurons' responses are fit equally well by models with either form of separability. However, responses to plaids (sums of two moving gratings) tend to be better described as velocity-separable, especially for pattern neurons. We conclude that direction selectivity in MT is primarily computed by summing V1 afferents, but pattern-invariant velocity tuning for complex stimuli may arise from local, recurrent interactions.Significance Statement How do sensory systems build representations of complex features from simpler ones? Visual motion representation in cortex is a well-studied example: the direction and speed of moving objects, regardless of shape or texture, is computed from the local motion of oriented edges. Here we quantify tuning properties based on single-unit recordings in primate area MT, then fit a novel, generalized model of motion computation. The model reveals two core properties of MT neurons - speed tuning and invariance to local edge orientation - result from a single organizing principle: each MT neuron combines afferents that represent edge motions consistent with a common velocity, much as V1 simple cells combine thalamic inputs consistent with a common orientation.
PMID: 31604815
ISSN: 2373-2822
CID: 4175542
Multimodal Hippocampal Subfield Grading For Alzheimer's Disease Classification
ISI:000487586600036
ISSN: 2045-2322
CID: 4155602
Ants as Emerging Models to Study Chemosensory Neuroplasticity [Meeting Abstract]
ISI:000493389500007
ISSN: 0379-864x
CID: 4221912
Principles and Techniques Applied to Enhance Elimination
New York : McGraw-Hill Education, [2019]
pp. ?-?
ISBN: 1259859614
CID: 3697902
The Spectrum of Neurobehavioral Outcomes in Attention-Deficit/Hyperactivity Disorder
Cham, Switzerland : Springer, [2019]
pp. 3-12
ISBN: 9783319949970
CID: 5301182
