Interplay of Race and Neighborhood Deprivation on Resting and Ambulatory Blood Pressure in Young Adults.

BACKGROUND: Nighttime BP and BP dipping (daytime-nighttime BP) are prognostic for cardiovascular disease. Compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping. Neighborhood deprivation may contribute to disparities in cardiovascular health, but its effects on resting and ambulatory BP patterns in young adults is unclear. Therefore, we examined associations between neighborhood deprivation with resting and nighttime BP and BP dipping in young Black and White adults. METHODS: We recruited 19 Black and 28 White participants (23 M/24 F, 21±1 years, body mass index: 26±4 kg/m2) for 24-hour ambulatory BP monitoring. We assessed resting BP, nighttime BP, and BP dipping (absolute dip and nighttime:daytime BP ratio). We used the area deprivation index (ADI) to assess average neighborhood deprivation during early- and mid-childhood, and adolescence. RESULTS: Compared with White participants, Black participants exhibited higher resting systolic and diastolic BP (ps≤0.029), nighttime systolic BP (114±9 vs. 108±9 mmHg, p=0.049), diastolic BP (63±8 vs. 57±7 mmHg, p=0.010), and attenuated absolute systolic BP dipping (12±5 vs. 9±7 mmHg, p=0.050). Black participants experienced greater average ADI scores compared with White participants (110(10) vs. 97(22), p=0.002), and select ADI scores correlated with resting BP and some ambulatory BP measures. Within each race, select ADI scores correlated with some BP measures for Black participants, but there were no ADI and BP correlations for White participants. CONCLUSIONS: Our findings suggest neighborhood deprivation may contribute to higher resting BP and impaired ambulatory BP patterns in young adults warranting further investigation in larger cohorts.

Acute high-dose MitoQ does not increase urinary kidney injury markers in healthy adults: a randomized crossover trial.

Several human studies have used the mitochondrial antioxidant MitoQ. Recent in vitro data indicating that MitoQ may induce nephrotoxicity caused concern regarding the safety of MitoQ on the kidneys, but the doses were supraphysiological. Therefore, we sought to determine whether acute MitoQ elicits changes in urinary biomarkers associated with tubular injury in healthy adults with our hypothesis being there would be no changes. Using a randomized crossover design, 32 healthy adults (16 females and 16 males, 29 ± 11 yr old) consumed MitoQ (100-160 mg based on body mass) or placebo capsules. We obtained serum samples and a 4- to 6-h postcapsule consumption urine sample. We assessed creatinine clearance and urine kidney injury biomarkers including the chitinase 3-like-1 gene product YKL-40, kidney-injury marker-1, monocyte chemoattractant protein-1, epidermal growth factor, neutrophil gelatinase-associated lipocalin, interleukin-18, and uromodulin using multiplex assays. We used t tests, Wilcoxon tests, and Hotelling's T2 to assess global differences in urinary kidney injury markers between conditions. Acute MitoQ supplementation did not influence urine flow rate (P = 0.086, rrb = 0.39), creatinine clearance (P = 0.085, rrb = 0.42), or urinary kidney injury markers (T22,8 = 30.6, P = 0.121, univariate ps > 0.064). Using exploratory univariate analysis, MitoQ did not alter individual injury markers compared with placebo (e.g., placebo vs. MitoQ: YKL-40, 507 ± 241 vs. 442 ± 236 pg/min, P = 0.241; kidney injury molecule-1, 84.1 ± 43.2 vs. 76.2 ± 51.2 pg/min, P = 0.890; and neutrophil gelatinase-associated lipocalin, 10.8 ± 10.1 vs. 9.83 ± 8.06 ng/min, P = 0.609). In conclusion, although longer-term surveillance and data are needed in clinical populations, our findings suggest that acute high-dose MitoQ had no effect on urinary kidney injury markers in healthy adults.NEW & NOTEWORTHY We found acute high-dose mitochondria-targeted antioxidant (MitoQ) supplementation was not nephrotoxic and had no effect on markers of acute kidney injury in healthy adults. These findings can help bolster further confidence in the safety of MitoQ, particularly for future investigations seeking to examine the role of mitochondrial oxidative stress, via acute MitoQ supplementation, on various physiological outcomes.

Adjusting for muscle strength and body size attenuates sex differences in the exercise pressor reflex in young adults.

Females typically exhibit lower blood pressure (BP) during exercise than males. However, recent findings indicate that adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI; metaboreflex isolation). In addition, body size is associated with HG strength but its contribution to sex differences in exercising BP is less appreciated. Therefore, the purpose of this study was to determine whether adjusting for strength and body size would attenuate sex differences in BP during HG and PEI. We obtained beat-to-beat BP in 110 participants (36 females, 74 males) who completed 2 min of isometric HG exercise at 40% of their maximal voluntary contraction followed by 3 min of PEI. In a subset (11 females, 17 males), we collected muscle sympathetic nerve activity (MSNA). Statistical analyses included independent t tests and mixed models (sex × time) with covariate adjustment for 40% HG force, height2, and body surface area. Females exhibited a lower absolute 40% HG force than male participants (Ps < 0.001). Females exhibited lower Δsystolic, Δdiastolic, and Δmean BPs during HG and PEI than males (e.g., PEI, Δsystolic BP, 15 ± 11 vs. 23 ± 14 mmHg; P = 0.004). After covariate adjustment, sex differences in BP responses were attenuated. There were no sex differences in MSNA. In a smaller strength-matched cohort, there was no sex × time interactions for BP responses (e.g., PEI systolic BP, P = 0.539; diastolic BP, P = 0.758). Our data indicate that sex differences in exercising BP responses are attenuated after adjusting for muscle strength and body size.NEW & NOTEWORTHY When compared with young males, females typically exhibit lower blood pressure (BP) during exercise. Adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI), but the contribution of body size is unknown. Novel findings include adjustments for muscle strength and body size attenuate sex differences in BP reactivity during exercise and PEI, and sex differences in body size contribute to HG strength differences.

Interplay of Race and Neighborhood Deprivation on Ambulatory Blood Pressure in Young Adults.

Background: Ambulatory blood pressure (BP) monitoring measures nighttime BP and BP dipping, which are superior to in-clinic BP for predicting cardiovascular disease (CVD), the leading cause of death in America. Compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping, including in young adulthood. Social determinants of health contribute to disparities in CVD risk, but the contribution of neighborhood deprivation on nighttime BP is unclear. Therefore, we examined associations between neighborhood deprivation with nighttime BP and BP dipping in young Black and White adults. Methods: We recruited 21 Black and 26 White participants (20 M/27 F, mean age: 21 years, body mass index: 25±4 kg/m2) for 24-hour ambulatory BP monitoring. We assessed nighttime BP and BP dipping (nighttime:daytime BP ratio). The area deprivation index (ADI) was used to measure neighborhood deprivation. Associations between ADI and ambulatory BP were examined. Results: Black participants exhibited higher nighttime diastolic BP compared with White participants (63±8 mmHg vs 58±7 mmHg, p=0.003), and attenuated BP dipping ratios for both systolic (0.92±0.06 vs 0.86±0.05, p=0.001) and diastolic BP (0.86±0.09 vs 0.78±0.08, p=0.007). Black participants experienced greater neighborhood deprivation compared with White participants (ADI scores: 110±8 vs 97±21, p<0.001), and ADI was associated with attenuated systolic BP dipping (ρ=0.342, p=0.019). Conclusions: Our findings suggest neighborhood deprivation may contribute to higher nighttime BP and attenuated BP dipping, which are prognostic of CVD, and more prevalent in Black adults. Targeted interventions to mitigate the effects of neighborhood deprivation may help to improve nighttime BP. Clinical Trial Registry: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04576338.

Cross-sectional analysis of racial differences in hydration and neighborhood deprivation in young adults.

BACKGROUND: Inadequate hydration is associated with cardiovascular and kidney disease morbidity and all-cause mortality. Compared with White individuals, Black individuals exhibit a higher prevalence of inadequate hydration, which may contribute to racial health disparities. However, the underlying reasons for these differences in hydration remain unclear. OBJECTIVE: This cross-sectional study aimed to investigate whether neighborhood deprivation contributes to racial differences in hydration status. METHODS: We assessed 24 Black and 30 White college students, measuring 24-hour urine osmolality, urine flow rate, urine specific gravity, and plasma copeptin concentration. Participants recorded their food and fluid intake for 3 d to assess total water intake from food and beverages. Neighborhood socioeconomic deprivation was measured using a tract-level Area Deprivation Index. RESULTS: Black participants exhibited higher urine osmolality (640 [314] compared with 440 [283] mOsm/kg H2O, respectively, P = 0.006) and lower urine flow rate (1.06 [0.65] compared with 1.71 [0.89] ml/min, respectively, P = 0.009) compared with White participants, indicating greater hypohydration among Black participants. Black participants reported lower total water intake from food and beverages than White participants (2.3 ± 0.7 compared with 3.5 ± 1.1 L/day, respectively, P < 0.01). Black participants exhibited higher copeptin than White participants (6.3 [3.1] compared with 4.5 [2.3] pmol/L, P = 0.046), and urine osmolality mediated 67% of the difference (P = 0.027). Black participants reported greater cumulative exposure to neighborhood deprivation during childhood (ages 0-18 y). Furthermore, neighborhood deprivation during childhood was associated with urine specific gravity (P = 0.031) and total water intake from food and beverages (P = 0.042) but did not mediate the racial differences in these measures. CONCLUSION: Our data suggest that compared with White young adults, Black young adults are hypohydrated and exhibit higher plasma copeptin concentration, and that greater neighborhood deprivation is associated with chronic underhydration irrespective of race. This trial was registered at clinicaltrials.gov as NCT04576338.

Ensemble Reweighting Using Cryo-EM Particle Images.

Cryo-electron microscopy (cryo-EM) has recently become a leading method for obtaining high-resolution structures of biological macromolecules. However, cryo-EM is limited to biomolecular samples with low conformational heterogeneity, where most conformations can be well-sampled at various projection angles. While cryo-EM provides single-molecule data for heterogeneous molecules, most existing reconstruction tools cannot retrieve the ensemble distribution of possible molecular conformations from these data. To overcome these limitations, we build on a previous Bayesian approach and develop an ensemble refinement framework that estimates the ensemble density from a set of cryo-EM particle images by reweighting a prior conformational ensemble, e.g., from molecular dynamics simulations or structure prediction tools. Our work provides a general approach to recovering the equilibrium probability density of the biomolecule directly in conformational space from single-molecule data. To validate the framework, we study the extraction of state populations and free energies for a simple toy model and from synthetic cryo-EM particle images of a simulated protein that explores multiple folded and unfolded conformations.

Eliminating Artificial Boundary Conditions in Time-Dependent Density Functional Theory Using Fourier Contour Deformation.

We present an efficient method for propagating the time-dependent Kohn-Sham equations in free space, based on the recently introduced Fourier contour deformation (FCD) approach. For potentials which are constant outside a bounded domain, FCD yields a high-order accurate numerical solution of the time-dependent Schrödinger equation directly in free space, without the need for artificial boundary conditions. Of the many existing artificial boundary condition schemes, FCD is most similar to an exact nonlocal transparent boundary condition, but it works directly on Cartesian grids in any dimension, and runs on top of the fast Fourier transform rather than fast algorithms for the application of nonlocal history integral operators. We adapt FCD to time-dependent density functional theory (TDDFT), and describe a simple algorithm to smoothly and automatically truncate long-range Coulomb-like potentials to a time-dependent constant outside of a bounded domain of interest, so that FCD can be used. This approach eliminates errors originating from the use of artificial boundary conditions, leaving only the error of the potential truncation, which is controlled and can be systematically reduced. The method enables accurate simulations of ultrastrong nonlinear electronic processes in molecular complexes in which the interference between bound and continuum states is of paramount importance. We demonstrate results for many-electron TDDFT calculations of absorption and strong field photoelectron spectra for one and two-dimensional models, and observe a significant reduction in the size of the computational domain required to achieve high quality results, as compared with the popular method of complex absorbing potentials.

High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults.

In rodents and older patients with elevated blood pressure (BP), high dietary sodium increases excretion of biomarkers of kidney injury, but it is unclear whether this effect occurs in healthy young adults. The purpose of this study was to determine whether short-term high dietary salt increases urinary excretion of the kidney injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in healthy young adults. Twenty participants participated in a double-blind, placebo-controlled, randomized crossover study. For 10 days each, participants were asked to consume salt (3,900 mg sodium) or placebo capsules. We measured BP during each visit, obtained 24-h urine samples for measurements of electrolytes, NGAL, and KIM-1, and assessed creatinine clearance. Compared with placebo, salt loading increased daily urinary sodium excretion (placebo: 130.3 ± 62.4 mmol/24 h vs. salt: 287.2 ± 72.0 mmol/24 h, P < 0.01). There was no difference in mean arterial BP (placebo: 77 ± 7 mmHg vs. salt: 77 ± 6 mmHg, P = 0.83) between conditions. However, salt loading increased the urinary NGAL excretion rate (placebo: 59.8 ± 44.4 ng/min vs. salt: 80.8 ± 49.5 ng/min, P < 0.01) and increased creatinine clearance (placebo: 110.5 ± 32.9 mL/min vs. salt: 145.0 ± 24.9 mL/min, P < 0.01). Urinary KIM-1 excretion was not different between conditions. In conclusion, in healthy young adults 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker NGAL but not KIM-1.NEW & NOTEWORTHY In healthy young adults, 10 days of dietary salt loading increased creatinine clearance and increased urinary excretion of the kidney injury biomarker marker neutrophil gelatinase-associated lipocalin despite no change in resting blood pressure.

A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments.

Cryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule's conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles. In this work, we propose the cryo-BIFE method (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. We test the framework on several synthetic systems where the imaging parameters and conditions were controlled. We found that for realistic cryo-EM environments and relevant biomolecular systems, it is possible to recover the underlying free energy, with the pose accuracy and SNR as crucial determinants. We then use the method to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of [Formula: see text]. We expect our tool for extracting free-energy profiles from cryo-EM images to enable more complete characterization of the thermodynamic ensemble of biomolecules.

SpikeForest, reproducible web-facing ground-truth validation of automated neural spike sorters.

Spike sorting is a crucial step in electrophysiological studies of neuronal activity. While many spike sorting packages are available, there is little consensus about which are most accurate under different experimental conditions. SpikeForest is an open-source and reproducible software suite that benchmarks the performance of automated spike sorting algorithms across an extensive, curated database of ground-truth electrophysiological recordings, displaying results interactively on a continuously-updating website. With contributions from eleven laboratories, our database currently comprises 650 recordings (1.3 TB total size) with around 35,000 ground-truth units. These data include paired intracellular/extracellular recordings and state-of-the-art simulated recordings. Ten of the most popular spike sorting codes are wrapped in a Python package and evaluated on a compute cluster using an automated pipeline. SpikeForest documents community progress in automated spike sorting, and guides neuroscientists to an optimal choice of sorter and parameters for a wide range of probes and brain regions.

High-Density, Long-Lasting, and Multi-region Electrophysiological Recordings Using Polymer Electrode Arrays.

The brain is a massive neuronal network, organized into anatomically distributed sub-circuits, with functionally relevant activity occurring at timescales ranging from milliseconds to years. Current methods to monitor neural activity, however, lack the necessary conjunction of anatomical spatial coverage, temporal resolution, and long-term stability to measure this distributed activity. Here we introduce a large-scale, multi-site, extracellular recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1,024 recording channels in freely behaving rats. This system can support months-long recordings from hundreds of well-isolated units across multiple brain regions. Moreover, these recordings are stable enough to track large numbers of single units for over a week. This platform enables large-scale electrophysiological interrogation of the fast dynamics and long-timescale evolution of anatomically distributed circuits, and thereby provides a new tool for understanding brain activity.

A Fully Automated Approach to Spike Sorting.

Understanding the detailed dynamics of neuronal networks will require the simultaneous measurement of spike trains from hundreds of neurons (or more). Currently, approaches to extracting spike times and labels from raw data are time consuming, lack standardization, and involve manual intervention, making it difficult to maintain data provenance and assess the quality of scientific results. Here, we describe an automated clustering approach and associated software package that addresses these problems and provides novel cluster quality metrics. We show that our approach has accuracy comparable to or exceeding that achieved using manual or semi-manual techniques with desktop central processing unit (CPU) runtimes faster than acquisition time for up to hundreds of electrodes. Moreover, a single choice of parameters in the algorithm is effective for a variety of electrode geometries and across multiple brain regions. This algorithm has the potential to enable reproducible and automated spike sorting of larger scale recordings than is currently possible.

Validation of neural spike sorting algorithms without ground-truth information.

BACKGROUND: The throughput of electrophysiological recording is growing rapidly, allowing thousands of simultaneous channels, and there is a growing variety of spike sorting algorithms designed to extract neural firing events from such data. This creates an urgent need for standardized, automatic evaluation of the quality of neural units output by such algorithms. NEW METHOD: We introduce a suite of validation metrics that assess the credibility of a given automatic spike sorting algorithm applied to a given dataset. By rerunning the spike sorter two or more times, the metrics measure stability under various perturbations consistent with variations in the data itself, making no assumptions about the internal workings of the algorithm, and minimal assumptions about the noise. RESULTS: We illustrate the new metrics on standard sorting algorithms applied to both in vivo and ex vivo recordings, including a time series with overlapping spikes. We compare the metrics to existing quality measures, and to ground-truth accuracy in simulated time series. We provide a software implementation. COMPARISON WITH EXISTING METHODS: Metrics have until now relied on ground-truth, simulated data, internal algorithm variables (e.g. cluster separation), or refractory violations. By contrast, by standardizing the interface, our metrics assess the reliability of any automatic algorithm without reference to internal variables (e.g. feature space) or physiological criteria. CONCLUSIONS: Stability is a prerequisite for reproducibility of results. Such metrics could reduce the significant human labor currently spent on validation, and should form an essential part of large-scale automated spike sorting and systematic benchmarking of algorithms.

Robust fast direct integral equation solver for quasi-periodic scattering problems with a large number of layers.

We present a new boundary integral formulation for time-harmonic wave diffraction from two-dimensional structures with many layers of arbitrary periodic shape, such as multilayer dielectric gratings in TM polarization. Our scheme is robust at all scattering parameters, unlike the conventional quasi-periodic Green's function method which fails whenever any of the layers approaches a Wood anomaly. We achieve this by a decomposition into near- and far-field contributions. The former uses the free-space Green's function in a second-kind integral equation on one period of the material interfaces and their immediate left and right neighbors; the latter uses proxy point sources and small least-squares solves (Schur complements) to represent the remaining contribution from distant copies. By using high-order discretization on interfaces (including those with corners), the number of unknowns per layer is kept small. We achieve overall linear complexity in the number of layers, by direct solution of the resulting block tridiagonal system. For device characterization we present an efficient method to sweep over multiple incident angles, and show a 25× speedup over solving each angle independently. We solve the scattering from a 1000-layer structure with 3 × 105 unknowns to 9-digit accuracy in 2.5 minutes on a desktop workstation.

Mechanistic home range models and resource selection analysis: a reconciliation and unification.

In the three decades since its introduction, resource selection analysis (RSA) has become a widespread method for analyzing spatial patterns of animal relocations obtained from telemetry studies. Recently, mechanistic home range models have been proposed as an alternative framework for studying patterns of animal space-use. In contrast to RSA models, mechanistic home range models are derived from underlying mechanistic descriptions of individual movement behavior and yield spatially explicit predictions for patterns of animal space-use. In addition, their mechanistic underpinning means that, unlike RSA, mechanistic home range models can also be used to predict changes in space-use following perturbation. In this paper, we develop a formal reconciliation between these two methods of home range analysis, showing how differences in the habitat preferences of individuals give rise to spatially explicit patterns of space-use. The resulting unified framework combines the simplicity of resource selection analysis with the spatially explicit and predictive capabilities of mechanistic home range models.

Analytic steady-state space use patterns and rapid computations in mechanistic home range analysis.

Mechanistic home range models are important tools in modeling animal dynamics in spatially complex environments. We introduce a class of stochastic models for animal movement in a habitat of varying preference. Such models interpolate between spatially implicit resource selection analysis (RSA) and advection-diffusion models, possessing these two models as limiting cases. We find a closed-form solution for the steady-state (equilibrium) probability distribution u using a factorization of the redistribution operator into symmetric and diagonal parts. How space use is controlled by the habitat preference function w depends on the characteristic width of the animals' redistribution kernel: when the redistribution kernel is wide relative to variation in w, u proportional, variant w, whereas when it is narrow relative to variation in w, u proportional, variant w (2). In addition, we analyze the behavior at discontinuities in w which occur at habitat type boundaries, and simulate the dynamics of space use given two-dimensional prey-availability data, exploring the effect of the redistribution kernel width. Our factorization allows such numerical simulations to be done extremely fast; we expect this to aid the computationally intensive task of model parameter fitting and inverse modeling.

Quantum mushroom billiards.

We report the first large-scale statistical study of very high-lying eigenmodes (quantum states) of the mushroom billiard proposed by L. A. Bunimovich [Chaos 11, 802 (2001)]. The phase space of this mixed system is unusual in that it has a single regular region and a single chaotic region, and no KAM hierarchy. We verify Percival's conjecture to high accuracy (1.7%). We propose a model for dynamical tunneling and show that it predicts well the chaotic components of predominantly regular modes. Our model explains our observed density of such superpositions dying as E(-1/3) (E is the eigenvalue). We compare eigenvalue spacing distributions against Random Matrix Theory expectations, using 16,000 odd modes (an order of magnitude more than any existing study). We outline new variants of mesh-free boundary collocation methods which enable us to achieve high accuracy and high mode numbers (approximately 10(5)) orders of magnitude faster than with competing methods.

Effective scattering coefficient of the cerebral spinal fluid in adult head models for diffuse optical imaging.

An efficient computation of the time-dependent forward solution for photon transport in a head model is a key capability for performing accurate inversion for functional diffuse optical imaging of the brain. The diffusion approximation to photon transport is much faster to simulate than the physically correct radiative transport equation (RTE); however, it is commonly assumed that scattering lengths must be much smaller than all system dimensions and all absorption lengths for the approximation to be accurate. Neither of these conditions is satisfied in the cerebrospinal fluid (CSF). Since line-of-sight distances in the CSF are small, of the order of a few millimeters, we explore the idea that the CSF scattering coefficient may be modeled by any value from zero up to the order of the typical inverse line-of-sight distance, or approximately 0.3 mm(-1), without significantly altering the calculated detector signals or the partial path lengths relevant for functional measurements. We demonstrate this in detail by using a Monte Carlo simulation of the RTE in a three-dimensional head model based on clinical magnetic resonance imaging data, with realistic optode geometries. Our findings lead us to expect that the diffusion approximation will be valid even in the presence of the CSF, with consequences for faster solution of the inverse problem.