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Accurate modeling of intermolecular repulsion is an integral component in force field development. Although repulsion can be explicitly calculated by applying the Pauli exclusion principle, this approach is computationally viable only for systems of limited sizes. Instead, it has previously been shown that repulsion can be reformulated in a "classical" picture: the Pauli exclusion principle prohibits electrons from occupying the same state, leading to a depletion of electronic charge between atoms, giving rise to an enhanced nuclear–nuclear electrostatic repulsion. This classical picture is called the isotropic S2/R approximation, where S is the overlap and R is the interatomic distance. This approximation accurately captures the repulsion of isotropic atoms such as noble gas dimers; however, a key deficiency is that it fails to capture the angular dependence of the repulsion of anisotropic molecules. To include directionality, the wave function must at least be a linear combination of s and p orbitals. We derive a new anisotropic S2/R repulsion model through the inclusion of the anisotropic p orbital term in the total wave function. Because repulsion is pairwise and decays rapidly, it can be truncated at a short range, making it amenable for efficient calculation of energy and forces in complex biomolecular systems. We present a parameterization of the S101 dimer database against the ab initio benchmark symmetry-adapted perturbation theory, which yields an rms error of only 0.9 kcal/mol. The importance of the anisotropic term is demonstrated through angular scans of water–water dimers and dimers involving halobenzene. Simulation of liquid water shows that the model can be computed efficiently for realistic system sizes. [ABSTRACT FROM AUTHOR]

Monitoring vegetation response to valley‐scale floodplain restoration to evaluate effectiveness can be costly and time‐consuming. We used publicly available National Agriculture Imagery Program (NAIP) data and commonly used ArcGIS software to assess land cover change over time at five study sites located in semi‐arid environments of eastern Oregon and north‐central California. Accuracy assessments of our unsupervised classifications were used to evaluate effectiveness. Overall accuracy across sites and years ranged from 64.2% to 89.2% with mean and median accuracy of 79.1% and 80.6%, respectively. Further, we compared our classifications with high‐resolution uncrewed aerial systems (UAS)‐based data collected in the same timeframe. Restored areas classified as dense vegetation were within 4% of the UAS study, water was within 6%, and post‐restoration classifications of sparse vegetation and bare ground classes were within 6% and 4% of the UAS study, respectively. This comparison demonstrates that our unsupervised NAIP data classification of land cover change across entire valley‐scale restoration projects can be used to monitor riparian vegetation change over time as accurately as UAS‐based methods, but at lower cost. Additionally, our methods leverage existing fine‐resolution, pre‐restoration vegetation density data that were not collected as part of project planning. [ABSTRACT FROM AUTHOR]

A growing body of research demonstrates that humans can accurately perceive the emotional states of animals solely by listening to their calls, highlighting shared evolutionary ancestry. Yet, the cognitive and perceptual mechanisms underlying heterospecific emotion perception have remained open to investigation. One hypothesis is that humans rely on simple acoustic heuristics to make such judgments, for example, perceiving higher-pitched calls as reflecting heightened emotional arousal (the "pitch rule"). This could lead to accurate judgments of emotion since in most mammals, as in humans, vocal fundamental frequency (the acoustic determinant of the pitch percept) does objectively correlate with emotional arousal. In the present study, we used digital pitch manipulation to create pairs of animal calls that were perceptually identical except for pitch, and we measured human perceptions of the caller's emotional arousal using an online survey. Calls of six phylogenetically diverse species were included as stimuli. Participants attributed slightly but statistically significantly higher arousal to higher-pitched versions of the same calls. Variation in application of the pitch rule across species was not well explained by familiarity, and prior experience with cats did not significantly predict sensitivity to pitch in cat vocalizations. Cross-species variation also did not align with phylogenetic distance from humans, or the hypothetical usefulness of pitch for making accurate judgments. Thus, the pitch rule may be a "mammalomorphic" heuristic leading to accurate emotion judgments in some taxa and call types and erroneous judgments in others, depending in part on phylogenetic distance and the mechanisms of call production. [ABSTRACT FROM AUTHOR]

A growing body of research demonstrates that humans can accurately perceive the emotional states of animals solely by listening to their calls, highlighting shared evolutionary ancestry. Yet, the cognitive and perceptual mechanisms underlying heterospecific emotion perception have remained open to investigation. One hypothesis is that humans rely on simple acoustic heuristics to make such judgments, for example, perceiving higher-pitched calls as reflecting heightened emotional arousal (the "pitch rule"). This could lead to accurate judgments of emotion since in most mammals, as in humans, vocal fundamental frequency (the acoustic determinant of the pitch percept) does objectively correlate with emotional arousal. In the present study, we used digital pitch manipulation to create pairs of animal calls that were perceptually identical except for pitch, and we measured human perceptions of the caller's emotional arousal using an online survey. Calls of six phylogenetically diverse species were included as stimuli. Participants attributed slightly but statistically significantly higher arousal to higher-pitched versions of the same calls. Variation in application of the pitch rule across species was not well explained by familiarity, and prior experience with cats did not significantly predict sensitivity to pitch in cat vocalizations. Cross-species variation also did not align with phylogenetic distance from humans, or the hypothetical usefulness of pitch for making accurate judgments. Thus, the pitch rule may be a "mammalomorphic" heuristic leading to accurate emotion judgments in some taxa and call types and erroneous judgments in others, depending in part on phylogenetic distance and the mechanisms of call production. [ABSTRACT FROM AUTHOR]

Simulating the dielectric spectra of solvents requires the nuanced definition of inter- and intra-molecular forces. Non-polarizable force fields, while thoroughly benchmarked for dielectric applications, do not capture all the spectral features of solvents, such as water. Conversely, polarizable force fields have been largely untested in the context of dielectric spectroscopy but include charge and dipole fluctuations that contribute to intermolecular interactions. We benchmark non-polarizable force fields and the polarizable force fields AMOEBA03 and HIPPO for liquid water and find that the polarizable force fields can capture all the experimentally observed spectral features with varying degrees of accuracy. However, the non-polarizable force fields miss at least one peak. To diagnose this deficiency, we decompose the liquid water spectra from polarizable force fields at multiple temperatures into static and induced dipole contributions and find that the peak originates from induced dipole contributions. Broadening our inquiry to other solvents parameterized with the AMOEBA09 force field, we demonstrate good agreement between the experimental and simulated dielectric spectra of methanol and formamide. To produce these spectra, we develop a new computational approach to calculate the dielectric spectrum via the fluctuation dissipation theorem. This method minimizes the error in both the low and high frequency portions of the spectrum, improving the overall accuracy of the simulated spectrum and broadening the computed frequency range. [ABSTRACT FROM AUTHOR]

Aerocapture is a promising orbit insertion strategy that can reduce propellant mass requirements for planetary orbiters. Reliable aerocapture requires active guidance, navigation, and control systems for robust performance. Such systems rely on accurate models of the downstream density environment for accurate targeting capabilities. Two density profile prediction techniques are introduced that use density histories computed from navigation measurements to improve aerocapture targeting accuracy: the density interpolator and the ensemble correlation filter. The density interpolator stores density data on the descent portion of the vehicle's trajectory, interpolating density values from this array during guidance predictions; whereas the ensemble correlation filter attempts to match density history data to onboard density profiles. A hybrid of the two methods is also considered. Both Earth and Venus are considered as planetary targets. A discrete-event control aerocapture scenario is considered, using Monte Carlo methods to assess the proposed methods' performances and demonstrate improvement in both the apoapsis error and entry corridor width. Density interpolator strategies were shown to perform consistently better than the density scale factor approaches. Ensemble correlation strategies were shown to provide a larger performance benefit potential as compared to interpolator strategies, particularly in cases where density model confidence is high. However, density interpolator strategies were shown to improve performance over a wider range of Monte Carlo simulation conditions. [ABSTRACT FROM AUTHOR]

Pauli repulsion is a key component of any theory of intermolecular interactions. Although Pauli or exchange repulsion has its origin in the quantum mechanical nature of electrons, it is possible to describe the resulting energetic effects via a classical model in terms of the overlap of electron densities. In fact, closed shell intermolecular repulsion can be explained as a diminution of election density in the internuclear region resulting in decreased screening of nuclear charges and increased nuclear-nuclear repulsion. We provide a concise anisotropic repulsion formulation using the atomic multipoles from the Atomic Multipole Optimized Energetics for Biomolecular Applications force field to describe the electron density at each atom in a larger system. Mathematically, the proposed model consists of damped pairwise exponential multipolar repulsion interactions truncated at short range, which are suitable for use in compute-intensive biomolecular force fields and molecular dynamics simulations. Parameters for 26 atom classes encompassing most organic molecules are derived from a fit to Symmetry Adapted Perturbation Theory exchange repulsion energies for the S101 dimer database. Several applications of the multipolar Pauli repulsion model are discussed, including noble gas interactions, analysis of stationary points on the water dimer potential surface, and the directionality of several halogen bonding interactions. [ABSTRACT FROM AUTHOR]

Grate and co-workers at Pacific Northwest National Laboratory recently developed high information content triazine-based sequence-defined polymers that are robust by not having hydrolyzable bonds and can encode structure and functionality by having various side chains. Through molecular dynamics (MD) simulations, the triazine polymers have been shown to form particular sequential stacks, have stable backbone-backbone interactions through hydrogen bonding and π–π interactions, and conserve their cis/trans conformations throughout the simulation. However, we do not know the effects of having different side chains and backbone structures on the entire conformation and whether the cis or trans conformation is more stable for the triazine polymers. For this reason, we investigate the role of non-covalent interactions for different side chains and backbone structures on the conformation and assembly of triazine polymers in MD simulations. Since there is a high energy barrier associated with the cis-trans isomerization, we use replica exchange molecular dynamics (REMD) to sample various conformations of triazine hexamers. To obtain rates and intermediate conformations, we use the recently developed concurrent adaptive sampling (CAS) algorithm for dimers of triazine trimers. We found that the hydrogen bonding ability of the backbone structure is critical for the triazine polymers to self-assemble into nanorod-like structures, rather than that of the side chains, which can help researchers design more robust materials. [ABSTRACT FROM AUTHOR]

Many montane tree species are expected to migrate upslope as climate warms, but it is not clear if forest canopy gaps, which can facilitate tree seedling recruitment, serve as an important mechanism driving tree species range shifts. Patterns of tree seedling establishment can inform us about early stages of tree species migrations and are critical to examine in the context of global climate change.We contrasted elevational distributions of tree seedlings both within and outside of forest canopy gaps with the distributions of conspecific adults and saplings across the deciduous‐coniferous ecotone on ten mountains in four states of the Northeastern United States. We tested if seedling distributions of four dominant tree species (Abies balsamea, Picea rubens, Acer saccharum and Fagus grandifolia) were shifted upslope of conspecific adult and sapling distributions. We also examined if this shift was facilitated by canopy gaps and what environmental drivers affected species distributions.There was limited seedling recruitment of dominant tree species at the temperate‐coniferous ecotone, which we attributed to (i) an observed downslope shift of seedling distributions of the low‐elevation deciduous species (Acer saccharum, Fagus grandifolia) and (ii) an upslope shift in seedling distributions of the high‐elevation conifers (Abies balsamea, Picea rubens). The upslope shift of conifer seedlings contrasts with our previous research at these sites which observed downslope shifts of sapling distributions in Picea rubens, suggesting that seedlings may be responding to more recent climate warming. Canopy gaps in high‐elevation conifer forests facilitated these upslope shifts by promoting conifer seedling recruitment. However, gaps at lower elevations did not play a significant role in seedling recruitment or the observed downslope shifts of the dominant deciduous species. Climate was the dominant predictor of adult tree distributions whereas both climate and soil were important predictors of seedling distributions.Synthesis. Our study illustrates that tree seedlings have the potential for monitoring the early stages of tree species migrations, and particularly so in canopy gaps in high‐elevation conifer forests. Further, we stress that species range shifts are sensitive to local scale heterogeneity in light availability (i.e. canopy gaps) and other non‐climatic factors. [ABSTRACT FROM AUTHOR]

Over the past few years, there has been an increased interest in large constellation architectures for different applications and services within the aerospace industry. Inherently, the growing attention to these complex systems comes with a desire for mission robustness and safety. Therefore, the aim of this paper is to enable a framework of necessary conditions to guarantee stability for formations with low levels of communication as well as low knowledge of control policies between users and formations with coordinated or uncoordinated impulsive maneuvers. A weighted formation barycenter and formation slots are presented to define the formation problem. Graph theory results are leveraged to demonstrate convergence on the consensus of the formation barycenter. Sufficient stability conditions are developed for different scenarios, and their performances are measured though a proposed formation error Lyapunov function. Analysis using the proposed Lyapunov formation error function shows that a democratic weighting scheme minimizes the formation error. An impulsive controller is presented to test the developed stability conditions. Simulations show the application of an impulsive decentralized control approach with sufficient stability conditions for different constellation scenarios; and it is validated that a democratic formation minimizes the formation error. [ABSTRACT FROM AUTHOR]

As Darwin first recognized, the study of emotional communication has the potential to improve scientific understanding of the mechanisms of signal production as well as how signals evolve. We examined the relationships between emotional arousal and selected acoustic characteristics of coo and scream vocalizations produced by female rhesus macaques, Macaca mulatta , during development. For coos, arousal was assessed through measures of stress-induced elevations of plasma cortisol exhibited in response to the human intruder test. In the analysis of screams, arousal was evaluated from the intensity of aggression experienced by the vocalizer during natural social interactions. Both call types showed a positive relationship between arousal and overall fundamental frequency (F0, perceived as pitch in humans). In coos, this association was dampened over development from infancy (6 months) to the juvenile, prepubertal period (16 months) and further to menarche (21.3–31.3 months), perhaps reflecting developmental changes in physiology, anatomy and/or call function. Heightened arousal was also associated in coos with increases in an acoustic dimension related to F0 modulation and noisiness. As monkeys matured, coos showed decreases in overall F0 as well as increased noisiness and F0 modulation, likely reflecting growth of the vocal apparatus and changes in vocal fold oscillation. Within screams, only one acoustic dimension (related to F0 modulation) showed developmental change, and only within one subclass of screams within one behavioural context. Our results regarding the acoustic correlates of arousal in both call types are broadly consistent with findings in other species, supporting the hypothesis of evolutionary continuity in emotion expression. We discuss implications for broader theories of how vocal acoustics respond to selection pressures. • Cortisol reactivity predicted fundamental frequency of coo calls. • Aggression severity predicted the fundamental frequency of scream calls. • Maturation to menarche yielded changes in acoustics and arousal expression. • Findings support phylogenetic continuity in vocal emotion expression. • Emotion may be a significant factor in the evolution of vocal acoustics. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations are useful in obtaining thermodynamic and kinetic properties of bio-molecules, but they are limited by the time scale barrier. That is, we may not obtain properties' efficiently because we need to run microseconds or longer simulations using femtosecond time steps. To overcome this time scale barrier, we can use the weighted ensemble (WE) method, a powerful enhanced sampling method that efficiently samples thermodynamic and kinetic properties. However, the WE method requires an appropriate partitioning of phase space into discrete macrostates, which can be problematic when we have a high-dimensional collective space or when little is known a priori about the molecular system. Hence, we developed a new WE-based method, called the "Concurrent Adaptive Sampling (CAS) algorithm," to tackle these issues. The CAS algorithm is not constrained to use only one or two collective variables, unlike most reaction coordinate-dependent methods. Instead, it can use a large number of collective variables and adaptive macrostates to enhance the sampling in the high-dimensional space. This is especially useful for systems in which we do not know what the right reaction coordinates are, in which case we can use many collective variables to sample conformations and pathways. In addition, a clustering technique based on the committor function is used to accelerate sampling the slowest process in the molecular system. In this paper, we introduce the new method and show results from two-dimensional models and bio-molecules, specifically penta-alanine and a triazine trimer. [ABSTRACT FROM AUTHOR]

Lymphedema surgeries have been proven effective in treating lymphedema and are not considered experimental or unproven. The medical literature consistently supports the safe and successful use of physiologic drainage lymphedema surgeries such as lymphaticovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), and reductive surgeries such as suction-assisted protein lipectomy (SAPL) when performed by an experienced lymphedema surgery team to treat properly selected patients. Proper integration of lymphedema therapy is critical to achieving successful outcomes. We review effective lymphedema surgeries, their indications, patient selection, and the proper application of surgical treatments to achieve optimal results. [ABSTRACT FROM AUTHOR]

Single-event, drag-modulated aerocapture has become a promising control scheme in the past decade. However, these architectures suffer from exhausted control authority post-jettison. Multiple drag-skirt jettison events have been shown to enhance aerocapture performance, yet still suffer from unidirectional control capabilities. An apoapsis target biasing method is introduced to improve multi-event, drag-modulated aerocapture accuracy and robustness. Entry trade studies and Monte Carlo methods are used for comparison to the state-of-the-art, assessing performance at 400 and 2000 km apoapsis targets and at entry flight path angles of -5.4° and -5.6°. Two ballistic coefficient ratio sets are investigated for both two- and three-stage separation event architectures. A two-stage architecture equipped with the biasing method is shown to be capable of reducing mean apoapsis error to zero, while also showing standard deviation reductions in apoapsis error and circularization Δv by 64.1 and 74.8%, respectively, compared with the state-of-the-art. A biased, three-stage architecture is shown to provide further benefit, reducing apoapsis error standard deviation by 70% relative to an equivalent unbiased architecture and 10.16% relative to a similarly sized two-stage architecture. [ABSTRACT FROM AUTHOR]

Sleep restriction (SR) (<6 h) and physical activity (PA) are risk factors for obesity, but little work has examined the inter‐related influences of both risk factors. In a free‐living environment, 13 overweight/obese adults were sleep restricted for five nights to 6 h time‐in‐bed each night, with and without regular exercise (45 min/65% VO2max; counterbalanced design). Two days of recovery sleep followed SR. Subjects were measured during a mixed meal tolerance test (MMT), resting metabolic rate, cognitive testing and fat biopsy (n=8). SR increased peak glucose response (+7.3 mg/dl, p =.04), elevated fasting non‐esterified fatty acid (NEFA) concentrations (+0.1 mmol/L, p =.001) and enhanced fat oxidation (p <.001) without modifying step counts or PA intensity. Inclusion of daily exercise increased step count (+4,700 steps/day, p <.001) and decreased the insulin response to a meal (p =.01) but did not prevent the increased peak glucose response or elevated NEFA levels. The weekend recovery period improved fasting glucose (p =.02), insulin (p =.02), NEFA concentrations (p =.001) and HOMA‐IR (p <.01) despite reduced steps (p <.01) and increased sedentary time (p <.01). Abdominal adipose tissue (AT) samples, obtained after baseline, SR and exercise, did not differ in lipolytic capacity following SR. Fatty acid synthase protein content tended to increase following SR (p =.07), but not following exercise. In a free‐living setting, SR adversely affected circulating NEFAs, fuel oxidation and peak glucose response but did not directly affect glucose tolerance or AT lipolysis. SR‐associated metabolic impairments were not mitigated by exercise, yet recovery sleep completely rescued its adverse effects on glucose metabolism. [ABSTRACT FROM AUTHOR]

Understanding the neural basis of brain function and dysfunction and designing effective therapeutics require high resolution targeted stimulation and recording of neural activity. Optical methods have been recently developed for neural stimulation as well as functional and structural imaging. These methods call for implantable devices to deliver light into the neural tissue at depth with high spatiotemporal resolution. To address this need, rigid and flexible neurophotonic implants have been recently designed. This article reviews the state-of-the-art flexible passive and active penetrating optical neural probes developed for light delivery with minimal damage to the tissue. Passive and active flexible neurophotonic implants are compared and insights about future directions are provided. [ABSTRACT FROM AUTHOR]

Purpose: Verification of patient position through pretreatment setup imaging is crucial in modern radiation therapy. As treatment complexity increases and technology evolves, physicist-physician collaboration becomes imperative for safe and successful radiation delivery. Despite the importance of both, residency programs lack formal interprofessional education (IPE) activities or structured training for image verification. Here we show the impact of an interprofessional image verification workshop for residents in a multi-institutional setting.Methods: The workshop included a lecture by the attending physicist and physician, and hands-on image registration practice by learners (medical physics residents, MP; and radiation oncology residents, RO). All participants filled out pre- and postactivity surveys and rated their comfort from 1 to 10 in (A) selecting what type of imaging to order for a given case and (B) independently assessing the setup quality based on imaging. A paired 1-tailed t test (α = 0.05) was used to evaluate significance; Spearman rank correlation coefficient was used to assess correlation of ratings and RO postgraduate year (PGY). Surveys had free-response questions about IPE and image verification activities in residency.Results: A total of 71 residents from 7 institutions participated between 2018 and 2020. Pre- and postsurveys were completed by 50 residents (38RO, 12MP) and showed an increase in (A) from 5.5 ± 2.2 to 7.1 ± 1.6 (P < .001) and in (B) from 5.1 ± 2.3 to 6.8 ± 1.5 (P < .001), with significant increases per subgroup (AΔ, RO = 1.8 ± 1.7, P < .001; BΔ, RO = 1.9 ± 1.8, P <. 001; AΔ, MP = 1.1 ± 1.4, P = .012; BΔ, MP = 1.2 ± 1.6, P = .016). RO confidence scores moderately correlated with PGY. Survey responses indicated that image verification training is mostly unstructured, with extent of exposure varying by program and attending; most with little-to-no training. Time constraints were identified as the main barrier. IPE was noted as a useful way to incorporate different perspectives into the process.Conclusions: Formal image verification training increases resident comfort with setup imaging review and provides opportunities for interprofessional collaboration in radiation oncology residency programs. [ABSTRACT FROM AUTHOR]

Objectives: Our research aims were to determine if repolarization measures (QTcF, QTcB, JTcF, and JTcB) in attention-deficit/hyperactivity disorder (ADHD) children and adolescents differ from normal subjects and determine if the JTc interval duration, as a purer repolarization measure than QTc, strengthens the differentiation between ADHD and normal children and adolescents. Methods: This study included 418 subjects aged 5-18 years who were diagnosed with ADHD, and 1948 subjects in a historical normal control group. One-way analysis of variance (ANOVA) was performed to compare the independent groups on normal continuous outcomes. Means and standard deviations (SDs) were reported and interpreted for the ANOVA. Logistic regression analysis was performed to test the ability of four variables (QTcB, QTcF, JTcB, and JTcF) to predict an ADHD diagnosis, with age and gender as independent covariates. The log odds with standard errors for each variable were reported and interpreted for the logistic models. Results: In the nominal logistic regressions with JTcF ≥322 or JTcB ≥335 (values 1 SD above the mean of the control group), age and sex were significant contributors to the models that showed that subjects with a JTcF ≥322 ms had a statistically and significantly higher probability to be diagnosed with ADHD in comparison with normal control subjects (odds ratio [OR]: 2.6, 95% confidence interval [95% CI] 2.02-3.33, p < 0.0001). Similarly, those subjects with a JTcB ≥335 ms were 2.7 times more likely to be diagnosed with ADHD than normal control subjects (OR: 2.7, 95% CI 2.1-3.45, p < 0.0001). Conclusions: JTc provided a clearer separation of the groups than QTc. JTcB and JTcF 1 SD above the control group means are strong predictors of ADHD diagnosis and remain so even when strong demographic predictors of longer QTc (age and sex) are included in the regression models. Consideration should be given to recording a pretreatment electrocardiogram in all children and adolescents with ADHD, and to measuring and monitoring JTc in patients with ADHD, especially when considering the addition of QT prolonging drugs. [ABSTRACT FROM AUTHOR]

The exploration of small bodies in our solar system is of great interest for the planetary science community due to their high scientific value. However, their generally weak and irregular gravity fields increase the difficulty associated with close proximity operations. Moreover, solar radiation pressure (SRP) can significantly perturb the motion of objects in their vicinity, particularly for bodies with high area-to-mass ratios. In this work, we adopt the polyhedral gravity model and identify natural dynamical structures that can be used for mission operations. Further, we study forced periodic motion in the body fixed frame while accounting for the effect of SRP with eclipses. Overall, our work seeks to identify suitable orbits and locations in the vicinity of small bodies that can be exploited for the design of science orbits. To obtain periodic orbits in the model accounting for SRP perturbations, we use a Melnikov function to find orbits that satisfy resonances with the asteroid spin and show no net change in energy over the orbit. We then use a differential correction scheme to find numerical solutions in the time-periodic model. Our test cases are potentially hazardous asteroid 101955 Bennu and main belt asteroid 16 Psyche. [ABSTRACT FROM AUTHOR]

Stem cells reside in and rely upon their niche to maintain stemness but must balance self-renewal with the production of daughters that leave the niche to differentiate. We discovered a mechanism of stem cell niche exit in the canonical C. elegans distal tip cell (DTC) germ stem cell niche mediated by previously unobserved, thin, membranous protrusions of the adjacent somatic gonad cell pair (Sh1). A disproportionate number of germ cell divisions were observed at the DTCSh1 interface. Stem-like and differentiating cell fates segregated across this boundary. Spindles polarized, pairs of daughter cells oriented between the DTC and Sh1, and Sh1 grew over the Sh1-facing daughter. Impeding Sh1 growth by RNAi to cofilin and Arp2/3 perturbed the DTC-Sh1 interface, reduced germ cell proliferation, and shifted a differentiation marker. Because Sh1 membrane protrusions eluded detection for decades, it is possible that similar structures actively regulate niche exit in other systems. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) organoid models derived from human pluripotent stem cells provide a platform for studying human development and understanding disease mechanisms. Most studies that examine biallelic inactivation of the cell cycle regulator Retinoblastoma 1 (RB1) and the link to retinoblastoma is in mice, however, less is known regarding the pathophysiological role of RB1 during human retinal development. To study the role of RB1 in early human retinal development and tumor formation, we generated retinal organoids from CRISPR/Cas9-derived RB1-null human embryonic stem cells (hESCs). We showed that RB is abundantly expressed in retinal progenitor cells in retinal organoids and loss of RB1 promotes S-phase entry. Furthermore, loss of RB1 resulted in widespread apoptosis and reduced the number of photoreceptor, ganglion, and bipolar cells. Interestingly, RB1 mutation in retinal organoids did not result in retinoblastoma formation in vitro or in the vitreous body of NOD/SCID immunodeficient mice. Together, our work identifies a crucial function for RB1 in human retinal development and suggests that RB1 deletion alone is not sufficient for tumor development, at least in human retinal organoids. A model of the role of RB1 during human retinal development. In wild-type cells, RB1 regulates entry into S-phase. While RB1 mutation in retinal organoids did not result in retinoblastoma formation, either in vitro or when injected into vitreous body of NOD/SCID mice, loss of RB1 promotes an accumulation of cells in S-phase, causes widespread apoptosis, and reduces the number of photoreceptor, ganglion and bipolar cells. Image 1 • RB expression is highest in progenitor cells and downregulated during maturation stages. • RB1 is required for S-phase entry and cell survival in retinal organoids. • RB1 is necessary for photoreceptor, ganglion and bipolar cell differentiation. • Loss of RB1 is not sufficient for retinoblastoma formation in retinal organoids. [ABSTRACT FROM AUTHOR]

Human screams have been suggested to comprise a salient and readily identified call type, yet few studies have explored the degree to which people agree on what constitutes a scream, and the defining acoustic structure of screams has not been fully determined. In this study, participants listened to 75 human vocal sounds, representing both a broad acoustical range and array of emotional contexts, and classified each as to whether it was a scream or not. Participants showed substantial agreement on which sounds were considered screams, consistent with the idea of screams as a basic call type. Agreement on classifications was related to participant gender, emotion processing accuracy, and empathy. To characterize the acoustic structure of screams, we measured the stimuli on 27 acoustic parameters. Principal components analysis and generalized linear mixed modeling indicated that classification as a scream was positively correlated with 3 acoustic dimensions: one corresponding to high pitch and roughness, another corresponding to wide fundamental frequency variability and narrow interquartile range bandwidth, and a third positively correlated with peak frequency slope. Twenty-six stimuli were agreed upon by > 90% of participants to be screams, but these were not acoustically homogeneous, and others evoked mixed responses. These results suggest that while screams might represent a salient and possibly innate call type, they also exhibit perceptual and acoustic gradation, perhaps reflecting the wide range of emotions and contexts in which they occur. [ABSTRACT FROM AUTHOR]

Background: In 2014, passive immunization by transfusion of Ebola convalescent plasma (ECP) was considered for treating patients with acute Ebola virus disease (EVD). Early Ebola virus (EBOV) seroconversion confers a survival advantage in natural infection, hence transfusion of ECP plasma with high levels of neutralizing EBOV antibodies is a potential passive immune therapy. Techniques to reduce the risk of other transfusion-transmitted infections (TTIs) are warranted as recent ECP survivors are ineligible as routine blood donors. As part of an ongoing clinical trial to evaluate the safety and effectiveness of ECP, the impact of amotosalen/UVA pathogen reduction technology (PRT) on EBOV antibody characteristics was examined.Study Design and Methods: Serum and plasma samples were collected from EVD-recovered subjects at multiple timepoints and evaluated by ELISA for antibodies to recombinant EBOV glycoprotein (GP) and irradiated whole EBOV antigen, as well as for EBOV microneutralization, classic plaque reduction neutralization test (PRNT) and EBOV pseudovirion neutralization assay (PsVNA) activity.Results: Six subjects donated 40 individual ECP units. Substantial antibody titers and neutralizing activity results were demonstrated but were generally lower for the ACD plasma samples compared to the serum samples. Anti-EBOV titers by all assays remained essentially unchanged after PRT.Conclusion: Treatment of ECP with PRT to reduce the risk of TTI did not significantly reduce EBOV IgG antibody titers or neutralizing activity. Although ECP was used in the treatment of repatriated patients, no PRT units from this study were transfused to EVD patients. This inventory of PRT-treated ECP is currently available for future clinical evaluation. [ABSTRACT FROM AUTHOR]

The dynamics of asteroid deflection and manipulation using mass ejection are examined. First, a linearized small angular velocity and inertia tensor deviation model for close-to-principal-axis rotators is developed. The model is then applied to launching boulders off of asteroid surfaces, proving that the principal-axis-rotator characteristic can be kept while removing material off the surface. Mass ejections for asteroid deflection are presented and examined. This method, dubbed mass driver deflection, uses small discrete launches of masses off an asteroid to prevent its collision with Earth. By using material from the asteroid itself, such as boulders or regolith deposits, mass driver deflection substantially reduces the required mass of the deflection system. The analysis in the paper seeks to optimize the deflection efforts while minimizing unwanted effects on the deflected asteroid's state: both rotational and orbital. The results show that deflection is possible in timeframes of several years in a variety of scenarios and that the deflection effects on the asteroid behavior do not pose a risk of disrupting the asteroid in a catastrophic way. [ABSTRACT FROM AUTHOR]

To evaluate the incidence and risk factors for lymphedema associated with surgery for gynecologic malignancies on GOG study 244. Women undergoing a lymph node dissection for endometrial, cervical, or vulvar cancer were eligible for enrollment. Leg volume was calculated from measurements at 10-cm intervals starting 10 cm above the bottom of the heel to the inguinal crease. Measurements were obtained preoperatively and postoperatively at 4–6 weeks, and at 3-, 6-, 9-, 12-, 18-, and 24- months. Lymphedema was defined as a limb volume change (LVC) ≥10% from baseline and categorized as mild: 10–19% LVC; moderate: 20–40% LVC; or severe: >40% LVC. Risk factors associated with lymphedema were also analyzed. Of 1054 women enrolled on study, 140 were inevaluable due to inadequate measurements or eligibility criteria. This left 734 endometrial, 138 cervical, and 42 vulvar patients evaluable for LVC assessment. Median age was 61 years (range, 28–91) in the endometrial, 44 years (range, 25–83) in the cervical, and 58 years (range, 35–88) in the vulvar group. The incidence of LVC ≥10% was 34% (n = 247), 35% (n = 48), and 43% (n = 18), respectively. The peak incidence of lymphedema was at the 4–6 week assessment. Logistic regression analysis showed a decreased risk with advanced age (p = 0.0467). An exploratory analysis in the endometrial cohort showed an increased risk with a node count >8 (p = 0.033). For a gynecologic cancer, LVC decreased with age greater than 65, but increased with a lymph node count greater than 8 in the endometrial cohort. There was no association with radiation or other risk factors. • Lymphedema as defined by volume change ≥10% was found in 34% of endometrial, 35% of cervical, and 43% of vulvar patients. • Regression analysis showed risk decreased with advanced age (p = 0.0467) and increased with a node count >8 (p = 0.033). • Increase risk of lymphedema was not associated with radiation, advanced stage or other commonly reported risk factors. • Final conclusions were weakened by 50% lost to follow-up and discrepancies in measurements identified in 32% of patients. [ABSTRACT FROM AUTHOR]

In this paper, we demonstrate that the uncertainty of the dual-satellite ephemeris must be included in order for the geolocation covariance to be accurate. Without the inclusion of this additional error source, the covariance is no longer consistent with the true uncertainty and can convey misleading results. The larger the uncertainty associated with the dual-satellite ephemeris the larger the geolocation covariance becomes. Therefore, we first demonstrate a technique for improving the dual-satellite ephemeris knowledge by using calibrator transmitters for orbit determination. Second, we derive a consider batch filter, which computes the best estimate of position of the unknown radio frequency source while taking into account the dual-satellite ephemeris uncertainty. An algorithm is also proposed for adding a probabilistic altitude constraint, which significantly reduces the solution error. Finally, we briefly touch upon a technique that allows for the dual-satellite ephemeris and source position to be estimated simultaneously thereby maintaining the correlations and optimality. All algorithms introduced have since been applied to real-world data and conveys actual capabilities rather than a theoretical approach alone. [ABSTRACT FROM AUTHOR]

Screams are phylogenetically widespread and typically associated with emotionally intense contexts, and thus present a window into the evolution of vocal emotion expression. Screams are distinct from other vocalizations, but nonetheless exhibit acoustic variation. The purpose of this study was to assess whether humans are sensitive to this variation, specifically, whether they base perceptions of screamer arousal on the pitch and/or duration of screams. A forced choice task revealed a significant tendency to perceive longer or higher-pitched (but otherwise acoustically identical) screams as more emotionally intense than shorter or lower-pitched screams, respectively. This pattern was independent of participants' gender, empathy score, and previous exposure to screams in the media. Furthermore, scream pairs exhibiting greater differences in duration yielded more consistent responses. Evolutionary implications relating to the acoustic correlates of arousal across mammalian species, as well as the socioecological functions of screams in other primates, are discussed. [ABSTRACT FROM AUTHOR]

A new model is presented to investigate the interaction between the asteroid's 6-degrees-of-freedom dynamics and the state of boulders on its surface. The model considers boulder motion on the surface of the asteroid as well as boulder launch, orbit, crash and escape in two ways. There are two mechanisms that change the angular velocity of the asteroid. First, there can be a momentum transfer during launch and crash of boulders, and second when a boulder moves the inertia tensor of the combined system changes. If a boulder launches and escapes the system, an effective Δ V is applied to the asteroid inertial velocity. By using defined polyhedral asteroid geometries and a given boulder distribution this hybrid model provides insight into the behavior of a specific asteroid while only accounting for tens or hundreds of bodies in the simulated system. This approach gives the model an advantage in detail in comparison to simpler analytical investigations, while also providing a computational advantage in comparison to a full N-body simulation. Surface moving boulders tend to reach the equator and launch from it or rest near it. The resulting orbits are of low inclination and follow chaotic trajectories leading to crash events. This model indicates that motion of several meter-sized boulders on the surface of a Bennu-like top-shaped asteroid can induce wobble in the spin axis on the order of 0.01° and a change of asteroid period on the order of several seconds. This phenomena, if it happens repeatedly, can alter the YORP and Yarkovsky evolution of small asteroids. • A model presents the interaction between an asteroid's rotation and surface. • The hybrid model shows advantages compared to analytical and N-body methods. • Boulder monition on asteroid surfaces changes rotation and can affect the orbit. [ABSTRACT FROM AUTHOR]

Numerous long-standing questions in origins-of-life research center on the history of biopolymers. For example, how and why did nature select the polypeptide backbone and proteinaceous side chains? Depsipeptides, containing both ester and amide linkages, have been proposed as ancestors of polypeptides. In this paper, we investigate cationic depsipeptides that form under mild dry-down reactions. We compare the oligomerization of various cationic amino acids, including the cationic proteinaceous amino acids (lysine, Lys; arginine, Arg; and histidine, His), along with nonproteinaceous analogs of Lys harboring fewer methylene groups in their side chains. These analogs, which have been discussed as potential prebiotic alternatives to Lys, are ornithine, 2,4-diaminobutyric acid, and 2,3-diaminopropionic acid (Orn, Dab, and Dpr). We observe that the proteinaceous amino acids condense more extensively than these nonproteinaceous amino acids. Orn and Dab readily cyclize into lactams, while Dab and Dpr condense less efficiently. Furthermore, the proteinaceous amino acids exhibit more selective oligomerization through their α-amines relative to their side-chain groups. This selectivity results in predominantly linear depsipeptides in which the amino acids are α-amine-linked, analogous to today's proteins. These results suggest a chemical basis for the selection of Lys, Arg, and His over other cationic amino acids for incorporation into proto-proteins on the early Earth. Given that electrostatics are key elements of protein-RNA and protein-DNA interactions in extant life, we hypothesize that cationic side chains incorporated into proto-peptides, as reported in this study, served in a variety of functions with ancestral nucleic acid polymers in the early stages of life. [ABSTRACT FROM AUTHOR]

This paper proposes an analytical formulation of the inertia parameters of Bezier shapes of arbitrary order. Bezier shapes can represent classical polyhedra as well as higher-order surface elements within the same framework. This formulation is linearized so as to yield the expressions of the first variation in the inertia properties of interest. These expressions eventually provide the second moment about the means of the inertia parameters, under the assumption of normally distributed, correlated mesh coordinates errors. This statistical model was evaluated over asteroid Itokawa and comet Churyumov–Gerasimenko, whose shape control points were subjected to a Gaussian, correlated deviation along their surface normals. The model exhibited good agreement with Monte-Carlo evaluations of the perturbed inertia moments, and should thus be of benefit to astronomers and astrodynamicists studying the dynamical environment of small bodies whose shape model is only known within some uncertainty. [ABSTRACT FROM AUTHOR]

Background and aims Deciduous angiosperm trees transport xylem sap through trunks and branches in vessels within annual growth rings. Utilizing previous growth rings for sap transport could increase vessel network size and redundancy but may expose new xylem to residual air embolisms in the network. Despite the important role of vessel networks in sap transport and drought resistance, our understanding of cross-ring connections within and between species is limited. Methods We studied cross-ring connections in four temperate deciduous trees using dye staining and X-ray microcomputed tomography (microCT) to detect xylem connectivity across growth rings and quantify their impact on hydraulic conductivity. Key results Acer rubrum and Fraxinus americana had cross-ring connections visible in microCT but only A. rubrum used previous growth rings for axial sap flow. Fagus grandifolia and Quercus rubra , however, did not have cross-ring connections. Accounting for the number of growth rings that function for axial transport improved hydraulic conductivity estimates. Conclusions These data suggest that the presence of cross-ring connections may help explain aspects of whole-tree xylem sap transport and should be considered for plant hydraulics measurements in these species and others with similar anatomy. [ABSTRACT FROM AUTHOR]

Since introduction of the International Conference on Harmonization proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of Torsade de Pointes. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a corrected QT (QTc) prolonging drug may be safe if it impacts multiple ion channels vs. only human ether‐a‐go‐go related gene (hERG) and that this effect can be discriminated using QT subintervals. We compared the predictive power of four electrocardiogram (ECG) repolarization metrics to discriminate single vs. multichannel block: (i) traditional 10‐second signal averaged triplicates, and (ii) three metrics that used increasing density of automatically measured beat‐to‐beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic (ROC) area under the curve (AUC). Compared with the traditional 10‐second signal averaged triplicates, the reduction in classification error ranged from 2−6 with increasing density of btb measurements. [ABSTRACT FROM AUTHOR]

Presents general methods for calculating the reaction field generated by a set of off-center point multipoles in a spherical cavity. Generalization of Kirkwood's original theory for an arbitrary charge distribution; Incorporation of reaction field effects in computation of induced dipole moments; Use of reaction field energy terms with empirical potential energy functions.

Considers the effect of viscosity variation on salt-finger instability in a fluid layer, a porous layer and their superposition. Existence of a mushy zone of dendrites and interdendritic liquid in the directional solidfication process of concentrated alloy undergoing solidification from below; Equations for the pure fluid layer; Equations and boundary conditions for pure porous layer case.

• Removal of distinct narrow-band peaks in frequency domain improves spike morphology. • Adaptive signal processing reduces electrical interference in ephys data. • Adaptive removal of electrical interference simplifies ephys data collection. Electrical interference from various sources is a common issue for experimental extracellular electrophysiology recordings collected using multi-electrode array neural recording systems. This interference deteriorates the signal-to-noise ratio (SNR) of the raw electrophysiology signals and hampers the accuracy of data post-processing using techniques such as spike-sorting. Traditional signal processing methods to digitally remove electrical interference during post-processing include bandpass filtering to limit the signal to the relevant spectral range of the biological data, e.g., the spikes band (300 Hz - 7 kHz), targeted notch filtering to remove power line interference from standard alternating current mains electricity and common reference removal to minimize noise common to all electrodes. These methods require a priori knowledge of the frequency of the interfering signal source to address the unique electromagnetic interference environment of each experimental setup. We discuss an adaptive method for automatically removing narrow-band electrical interference through a spectral peak detection and removal (SPDR) step that can be applied during post-processing of the recorded data, based on the intuition that tall, narrowband signals localized in the signal spectrum correspond to interference, rather than the activity of neurons. A spectral peak prominence (SPP) threshold is used to detect these peaks in the frequency domain, which will then be removed via notch filtering. We applied this method to simulated waveforms and also experimental electrophysiology data collected from cerebral organoids to demonstrate its effectiveness for removing unwanted interference without significantly distorting the neural signals. We discuss that proper selection of the SPP threshold is required to avoid over-filtering, which can result in distortion of the electrophysiology data. We also compare the firing-rate activity in the filtered electrophysiology with fluorescence calcium imaging, a secondary cellular activity marker, to quantify signal distortion and provide bounds on SNR-based optimization of the SPP threshold. The adaptive filtering technique demonstrated in this paper is a powerful method that can automatically detect and remove interband interference in recorded neural signals, potentially enabling data collection in more naturalistic settings where external interference signals are difficult to eliminate. [ABSTRACT FROM AUTHOR]

The optimization of a hypersonic glide vehicle's reachable domain is studied using different models to constrain the stagnation-point heat transfer. The vehicle is modeled as a high-lift common aero vehicle that uses bank-angle modulation for crossrange maneuvering with a leading-edge thermal protection system made of an ultra-high-temperature ceramic. A constrained nonlinear optimization problem is formulated to determine the range of feasible trajectories that satisfy aerodynamic heating and loading constraints. The optimal control profile is determined using a modified particle swarm optimization routine that employs a penalty function approach to handle path and terminal constraints. Baseline trajectories are determined using an existing convective heat-flux correlation, and the effect of surface catalycity on the optimized trajectories is investigated by applying a correction factor, derived from high-fidelity computational fluid dynamics simulations, to the heat-flux correlation. Results demonstrate a high sensitivity of the optimized trajectories to the underlying aerothermodynamics model such that accounting for surface catalycity expands the reachability by an order of magnitude. [ABSTRACT FROM AUTHOR]

The purpose of this study was to measure the electrocardiographic (ECG) effects of WCK 2349 (the L‐alanine ester prodrug of levonadifloxacin) at a supratherapeutic oral dose of 2,600 mg. A total of 48 healthy volunteers were randomized to treatment with placebo, WCK 2349, or oral moxifloxacin, 400 mg, in a crossover‐designed thorough QT study. A supratherapeutic mean maximum levonadifloxacin concentration (Cmax) of 43.3 μg/mL was achieved at 3.1 hours. A therapeutic dose of 1,000 mg b.i.d. in a previous study in patients resulted in a Cmax of 17.8 μg/mL. WCK 2349 exerted no significant effect on baseline‐ and placebo‐corrected QTcF (QT interval corrected for heart rate (HR) by the Fridericia formula), QRS, or PR interval. HR was transiently accelerated by a maximum of 14.4 (95% confidence interval, 11.80–16.92) beats per minute (bpm) at 3 hours. Concentration–effect modeling predicted a mean increase of 8.0 bpm at Cmax at the standard therapeutic dose. A therapeutic dose of 1,000 mg b.i.d. of WCK 2349 is not expected to cause clinically significant ECG effects, except for a possible transient increase in HR, which seems to be clinically insignificant. [ABSTRACT FROM AUTHOR]

Potential effects on cardiac repolarization of single doses of moxidectin, a potent long‐acting macrocyclic lactone endectocide, were assessed in a concentration‐QT (c‐QT; exposure‐response) study. This double‐blind, placebo‐controlled, parallel‐group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval‐plasma concentration time‐matched pairs. Moxidectin had no statistically significant or clinically relevant impact on QT interval at any dose level. The primary mixed effects model analysis revealed no treatment‐related impact on the Fridericia‐corrected QT interval‐plasma concentration gradient (−0.0077, 90% confidence interval (CI) −0.0255 to +0.0101). [ABSTRACT FROM AUTHOR]

Abstract We have successfully integrated techniques for controlling cell adhesion and performing electrochemical differential pulse voltammetry (DPV) through the use of digitally controlled microfluidics and patterned transparent indium tin oxide electrode arrays to enable rapid and sensitive enumeration of cancer cells in a scalable microscale format. This integrated approach leverages a dual-working electrode (WE) surface to improve the specificity of the detection system. Here, one of the WE surfaces is functionalized with anti-Melanocortin 1 Receptor antibodies specific to melanoma cancer cells, while the other WE acts as a control (i.e., without antibody), for detecting non-specific interactions between cells and the electrode. The method is described and shown to provide effective detection of melanoma cells at concentrations ranging between 25 and 300 cells per 20 μL sample volume after a 5 min incubation and 15 s of DPV measurements. The estimated limit of detection was ∼17 cells. The sensitivity and specificity of the assay were quantified using addition of large fractions of non-target cells and resulted in a detection reproducibility of ∼97%. The proposed approach demonstrates a unique integration of electrochemical sensing and microfluidic cell adhesion technologies with multiple advantages such as label-free detection, short detection times, and low sample volumes. Next steps for this platform include testing with patient samples and use of other cell-surface biomarkers for detection and enumeration of circulating tumor cells in prostate, breast, and colon cancer. Graphical abstract Integrated technique for controlling cell adhesion and performing electrochemical differential pulse voltammetry (DPV) through the use of digitally controlled microfluidics and patterned transparent indium tin oxide (ITO) electrode arrays to enable rapid and sensitive enumeration of melanoma cells in a scalable microscale format. Image 1 Highlights • Integration of microfluidics to enhance label-free electrochemical sensing. • Label-free detection and enumeration of melanoma cells in a scalable microscale format. • Rapid detection of as few as 25 cells in ∼5 min with an LOD of ∼17 cells. • Potential portable point-of-care system for routine monitoring of rare cell types. [ABSTRACT FROM AUTHOR]

Summary: During drought, xylem sap pressures can approach or exceed critical thresholds where gas embolisms form and propagate through the xylem network, leading to systemic hydraulic dysfunction. The vulnerability segmentation hypothesis (VSH) predicts that low‐investment organs (e.g. leaf petioles) should be more vulnerable to embolism spread compared to high‐investment, perennial organs (e.g. trunks, stems), as a means of mitigating embolism spread and excessive negative pressures in the perennial organs. We tested this hypothesis by measuring air‐seeding thresholds using the single‐vessel air‐injection method and calculating hydraulic safety margins in four northern hardwood tree species of the northeastern United States, in both saplings and canopy height trees, and at five points along the soil–plant–atmosphere continuum. Acer rubrum was the most resistant to air‐seeding and generally supported the VSH. However, Fagus grandifolia, Fraxinus americana and Quercus rubra showed little to no variation in air‐seeding thresholds across organ types within each species. Leaf‐petiole xylem operated at water potentials close to or exceeding their hydraulic safety margins in all species, whereas roots, trunks and stems of A. rubrum, F. grandifolia and Q. rubra operated within their safety margins, even during the third‐driest summer in the last 100 yr. [ABSTRACT FROM AUTHOR]

The Human Cell Atlas is a large, international consortium that aims to identify and describe every cell type in the human body. The comprehensive cellular maps that arise from this ambitious effort have the potential to transform many aspects of fundamental biology and clinical practice. Here, we discuss the technical approaches that could be used today to generate such a resource and also the technical challenges that will be encountered. [ABSTRACT FROM AUTHOR]

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown.Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes.Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 (-10%; P = 0.01). Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P = 0.08). No treatment changes were seen in uveoscleral outflow rate.Conclusions: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways. [ABSTRACT FROM AUTHOR]

With the increased emphasis on sustainability and place-based education, along with a heightened sense of awareness of diversity and inclusion issues in outdoor education, the time has come to critically examine the long-held trip and expedition construct within the outdoor education field. This paper will explore the theoretical influences of Romanticism on the field and connect these influences to long-standing and unresolved issues of diversity and inclusion in outdoor education. Using the romantic concept of the "sublime," I argue that outdoor and adventure education have traditionally settled around the organizing motif of the trip and the expedition in contrast with local and everyday experiences, and as a result, these frameworks have caused the field to miss opportunities for wider acceptance and usage as well as solidarity with like-minded pedagogies in environmental and place-based education. In this paper, I claim that a critical awareness of the romantic legacy, combined with a renewed focus on the concept of place and everyday experiences, will allow the fields of outdoor and adventure education to expand in influence and inclusion. [ABSTRACT FROM AUTHOR]

Tree-growth responses to environmental change could provide early detection of shifts in forest composition and help facilitate ecosystem management and conservation., We studied forest tree responses to recent trends in climate and acidic deposition using analyses of tree rings and long-term climate, deposition and forest plot data along an elevational climatic gradient in the northeastern United States. We analysed how (i) individual growth of dominant species ( Picea rubens, Abies balsamea) and (ii) spatial distributions of all species, changed with elevation over time due to changing environment., We observed a mean 220 m upslope shift of temperature envelopes since the 1960s, consistent with regional climate warming, but found no evidence of synchronous upslope shifts in species abundance. Species' ranges were stable although some leaned upslope or downslope, suggesting species-specific migration lags or controls on species' ranges., Compared to species distributions, the growth of dominant species was more responsive to environmental change. Although the basal area of P. rubens declined within its range since the 1960s, its growth has increased recently with increasing precipitation pH and to a lesser extent with warming climate. Abies balsamea has gradually increased in both basal area and density since the 1960s, with its growth responding to precipitation pH but not climate. Historically, P. rubens grew better at lower and A. balsamea at higher elevations, but these elevation effects appeared to be mediated primarily by moisture, and have disappeared over time., Synthesis and applications. Mean tree-growth responses to changing climate (temperature, moisture) and precipitation chemistry were more consistent and more clearly detectable than shifts in tree species' ranges, suggesting that monitoring tree growth across climatically controlled species' ranges (e.g. along elevational or latitudinal gradients) may provide a powerful tool for early detection of potential future changes in forest composition in a changing environment. [ABSTRACT FROM AUTHOR]

Mountains contain steep but constricted climate gradients that can provide climate warming refugia often overlooked in coarse-scale models of species migrations. With continued climate warming, the potentially important role of mountains in maintaining suitable climate for migrating species is still not clear. To determine if mountains in the northeastern U.S. can continue to serve as refugia for species in high-elevation spruce-fir forests under warming climate, we studied climate and climate-vegetation relations along elevational gradients across 76 sites on 11 mountains in four states of this region. We calculated (a) fine-scale temperature lapse rates using in situ climate loggers on each mountain, and (b) regional long-term temperature trends using 36 meteorological stations, in order to determine (c) recent and expected future shifts in species temperature envelopes along elevational gradients by linking lapse rates with regional temperature trends and climate warming scenarios for 2100 (+1, 3, and 5 °C). Since 1960, temperature regimes have shifted upslope on average by 377 m and 133 m for the monthly mean of daily minimum (T min ) and maximum (T max ) temperatures, respectively, although climate did not warm equally for all months. By 2100, mid-range warming of 3 °C may shift monthly temperature regimes upslope relative to their 1960s locations on average by 986 m for T min (580 m for 1 °C, and 1393 m for 5 °C scenario) and 588 m for T max (285 m for 1 °C, and 891 m for 5 °C scenario). We confirmed that spruce-fir forest distribution in the northeastern U.S. is strongly related to temperature, particularly October T max that has surprisingly differed from the overall warming trend as it cooled slightly since the 1960s and thus possibly contributed to the recent downslope shifts in some species ranges documented across the region in other studies. However, the vast majority of monthly temperature variables suggest considerable climate warming since the 1960s, and, given the expected future warming, the temperature regimes characteristic of the lower range margin of spruce-fir forests are unlikely to be present on many mountains in the region by 2100. Consequently, mountains in the northeastern U.S. may not provide long-term climate refugia for species dependent on the climate currently found in spruce-fir forests unless they can adapt to warmer temperatures. [ABSTRACT FROM AUTHOR]

Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21-knockout (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n = 9-15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR) and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects. [ABSTRACT FROM AUTHOR]