Author Correction: Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Diffusion-tensor-imaging 1-year-old and 2-year-old infant brain atlases with comprehensive gray and white matter labels.

Human infancy is marked by fastest postnatal brain structural changes. It also coincides with the onset of many neurodevelopmental disorders. Atlas-based automated structure labeling has been widely used for analyzing various neuroimaging data. However, the relatively large and nonlinear neuroanatomical differences between infant and adult brains can lead to significant offsets of the labeled structures in infant brains when adult brain atlas is used. Age-specific 1- and 2-year-old brain atlases covering all major gray and white matter (GM and WM) structures with diffusion tensor imaging (DTI) and structural MRI are critical for precision medicine for infant population yet have not been established. In this study, high-quality DTI and structural MRI data were obtained from 50 healthy children to build up three-dimensional age-specific 1- and 2-year-old brain templates and atlases. Age-specific templates include a single-subject template as well as two population-averaged templates from linear and nonlinear transformation, respectively. Each age-specific atlas consists of 124 comprehensively labeled major GM and WM structures, including 52 cerebral cortical, 10 deep GM, 40 WM, and 22 brainstem and cerebellar structures. When combined with appropriate registration methods, the established atlases can be used for highly accurate automatic labeling of any given infant brain MRI. We demonstrated that one can automatically and effectively delineate deep WM microstructural development from 3 to 38 months by using these age-specific atlases. These established 1- and 2-year-old infant brain DTI atlases can advance our understanding of typical brain development and serve as clinical anatomical references for brain disorders during infancy.

Neural-Cell-Intrinsic NF-κB Signaling Enhances Reovirus Virulence.

Pathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germ line ablation of NF-κB subunit p50. It is not known whether the proapoptotic function of NF-κB is mediated by neural-cell-intrinsic (neural-intrinsic) processes, NF-κB-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-κB signaling in reovirus-induced neuronal injury, we established mice that lack NF-κB p65 expression in neural cells using the Cre/loxP recombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural cell NF-κB p65 (Nsp65-/-) survived. While viral loads in brains of WT and Nsp65-/- mice were comparable, histological analysis revealed that reovirus antigen-positive areas in the brains of WT mice displayed increased immunoreactivity for cleaved caspase-3, a marker of apoptosis, relative to Nsp65-/- mice. These data suggest that neural-intrinsic NF-κB-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected brain cortices of WT and Nsp65-/- mice suggests that NF-κB activation in neuronal cells upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-κB-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations. IMPORTANCE Viral encephalitis contributes to illness and death in children and adults worldwide and has limited treatment options. Identifying common host factors upregulated by neurotropic viruses can enhance an understanding of virus-induced neuropathogenesis and aid in development of therapeutics. Although many neurotropic viruses activate NF-κB during infection, mechanisms by which NF-κB regulates viral neuropathogenesis and contributes to viral encephalitis are not well understood. We established mice in which NF-κB expression is ablated in neural tissue to study the function of NF-κB in reovirus neurovirulence and identify genes activated by NF-κB in response to reovirus infection in the central nervous system. Encephalitis following reovirus infection was dampened in mice lacking neural cell NF-κB. Reovirus induced a chemokine profile in the brain that was dependent on NF-κB signaling and was similar to chemokine profiles elicited by other neurotropic viruses. These data suggest common underlying mechanisms of encephalitis caused by neurotropic viruses and potentially shared therapeutic targets.

Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40.

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

Multiple images captured from a single encounter do not promote face learning.

Viewing multiple images of a newly encountered face improves recognition of that identity in new instances. Studies examining face learning have presented high-variability (HV) images that incorporate changes that occur from moment-to-moment (e.g., head orientation and expression) and over time (e.g., lighting, hairstyle, and health). We examined whether low-variability (LV) images (i.e., images that incorporate only moment-to-moment changes) also promote generalisation of learning such that novel instances are recognised. Participants viewed a single image, six LV images, or six HV images of a target identity before being asked to recognise novel images of that identity in a face matching task (training stimuli remained visible) or a memory task (training stimuli were removed). In Experiment 1 (n = 71), participants indicated which image(s) in 8-image arrays belonged to the target identity. In Experiment 2 (n = 73), participants indicated whether sequentially presented images belonged to the target identity. Relative to the single-image condition, sensitivity to identity improved and response biases were less conservative in the HV condition; we found no evidence of generalisation of learning in the LV condition regardless of testing protocol. Our findings suggest that day-to-day variability in appearance plays an essential role in acquiring expertise with a novel face.

The psychometrics of rating facial attractiveness using different response scales.

Perceiving facial attractiveness is an important behaviour across psychological science due to these judgments having real-world consequences. However, there is little consensus on the measurement of this behaviour, and practices differ widely. Research typically asks participants to provide ratings of attractiveness across a multitude of different response scales, with little consideration of the psychometric properties of these scales. Here, we make psychometric comparisons across nine different response scales. Specifically, we analysed the psychometric properties of a binary response, a 0-100 scale, a visual analogue scale, and a set of Likert scales (1-3, 1-5, 1-7, 1-8, 1-9, 1-10) as tools to measure attractiveness, calculating a range of commonly used statistics for each. While certain properties suggested researchers might choose to favour the 1-5, 1-7 and 1-8 scales, we generally found little evidence of an advantage for one scale over any other. Taken together, our investigation provides consideration of currently used techniques for measuring facial attractiveness and makes recommendations for researchers in this field.

Social determinants of health and treatment center affiliation: analysis from the sickle cell disease implementation consortium registry.

BACKGROUND: Adults with sickle cell disease (SCD) suffer early mortality and high morbidity. Many are not affiliated with SCD centers, defined as no ambulatory visit with a SCD specialist in 2 years. Negative social determinants of health (SDOH) can impair access to care. HYPOTHESIS: Negative SDOH are more likely to be experienced by unaffiliated adults than adults who regularly receive expert SCD care. METHODS: Cross-sectional analysis of the SCD Implementation Consortium (SCDIC) Registry, a convenience sample at 8 academic SCD centers in 2017-2019. A Distressed Communities Index (DCI) score was assigned to each registry member's zip code. Insurance status and other barriers to care were self-reported. Most patients were enrolled in the clinic or hospital setting. RESULTS: The SCDIC Registry enrolled 288 Unaffiliated and 2110 Affiliated SCD patients, ages 15-45y. The highest DCI quintile accounted for 39% of both Unaffiliated and Affiliated patients. Lack of health insurance was reported by 19% of Unaffiliated versus 7% of Affiliated patients. The most frequently selected barriers to care for both groups were "previous bad experience with the healthcare system" (40%) and "Worry about Cost" (17%). SCD co-morbidities had no straightforward trend of association with Unaffiliated status. The 8 sites' results varied. CONCLUSION: The DCI economic measure of SDOH was not associated with Unaffiliated status of patients recruited in the health care delivery setting. SCDIC Registrants reside in more distressed communities than other Americans. Other SDOH themes of affordability and negative experiences might contribute to Unaffiliated status. Recruiting Unaffiliated SCD patients to care might benefit from systems adopting value-based patient-centered solutions.

Through the sensor estimation of sound speed profiles.

A through-the-sensor method to sense the local sound speed profile (SSP) using measured acoustic wave numbers via an array of hydrophones is proposed. Ocean sounds can be treated as acoustic energy trapped as discrete modes within the water column. A Fredholm integral equation of the first kind relates the linearized (perturbative) sound speed corrections to the wave number differences between the measured values and those calculated from an acoustic kernel. Thus, a method to exploit environmental information deduced from different in situ sonar systems is proposed. Though this inversion can be unstable and non-unique, recent improvements in sparse inversions can lead to robust estimates even without an accurate starting SSP. An iterative algorithm using multiple acoustic frequencies is beneficial to achieve convergence and stability for larger sound speed corrections. This paper will compare broadband incoherent L2- and coherent L1-inversion results. Careful consideration must be made of the acoustic frequency, number of modes, a priori environmental information (e.g., water depth), and array length. The method will be first demonstrated on simulations and recordings from the Littoral Depth Discrimination Experiment 2012 (LIDDEX12) data set.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Impact of National Institutes of Health and Food and Drug Administration Tobacco Research Funding: A Bibliometrics Analyses.

INTRODUCTION: Conduct bibliometric analyses documenting the output of National Institutes of Health (NIH) tobacco-related and Food and Drug Administration (FDA) tobacco regulatory science (FDA-TRS) research portfolios. AIMS AND METHODS: PubMed identifiers for publications between 2015 and 2020 citing tobacco funding by NIH and/or FDA were imported into NIH iCite generating measures of productivity and influence, including number of citations, journal, relative citation ratios (RCR), and comparison of research influence across Web of Science (WoS) disciplines. Coauthorship and measures of centrality among and between NIH and FDA-supported investigators gauged collaboration. RESULTS: Between FY 2015 and 2020, 8160 publications cited funding from NIH tobacco-related grants, 1776 cited FDA-TRS grants and 496 cited Common funding (ie, both NIH and FDA-TRS funding). The proportion of publications citing NIH grants declined while those citing FDA-TRS or Common funding rose significantly. Publications citing Common funding showed the highest influence (mean RCR = 2.52). Publications citing FDA-TRS funding displayed higher median RCRs than publications citing NIH funding in most WoS categories. Higher translational progress was estimated over time for FDA-TRS and Common publications compared to NIH publications. Authors citing Common funding scored highest across all collaboration measures. CONCLUSIONS: This study demonstrates the high bibliometric output of tobacco research overall. The rise in publications citing FDA-TRS and Common likely reflects increased funding for TRS research. Higher RCRs across WoS subject categories and trends towards human translation among FDA-TRS and Common publications indicate focus on research to inform regulation. This analysis suggests that FDA support for TRS has expanded the field of tobacco control resulting in sustained productivity, influence, and collaboration. IMPLICATIONS: This paper is the first effort to better describe the impact of tobacco research resulting from the addition of FDA funding for TRS in the past decade. The analysis provides impetus for further investigation into the publication topics and their focus which would offer insight into the specific evidence generated on tobacco control and regulation.

Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.

Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.

Impaired insulin signaling at the bladder mucosa facilitates metabolic syndrome-associated bladder overactivity in rats with maternal and post-weaning fructose exposure.

BACKGROUND/PURPOSE: Metabolic syndrome (MetS) and overactive bladder might share common pathophysiologies. Environmental fructose exposure during pre- and postnatal periods of rats may program MetS-associated bladder overactivity. We explored the dysregulated insulin signalling at bladder mucosa, as a common mechanism, in facilitating bladder overactivity in rats with MetS induced by maternal and post-weaning fructose diet. METHODS: Male offspring of Sprague-Dawley rats were subject into 4 groups by maternal and post-weaning diets (i.e., Control/Control, Fructose/Control, Control/Fructose and Fructose/Fructose by diets). Micturition behavior was evaluated. Acidic ATP solution was used to elicit cystometric reflex along with insulin counteraction. Concentration-response curves to insulin were plotted. The canonical signalling pathway of insulin was evaluated in the bladder mucosal using Western blotting. Levels of detrusor cGMP and urinary NO2 plus NO3 were measured. RESULTS: Male offspring with any fructose exposure presents traits of MetS and bladder overactivity. We observed all fructose exposure groups have the poor urodynamic response to insulin during ATP solution stimulation and poor insulin-activated detrusor relaxation in organ bath study. Compared to controls, the Control/Fructose and Fructose/Fructose groups showed the increased phosphorylation levels of IRS1 (Ser307) and IRS2 (Ser731); thus, suppressed the downstream effectors and urinary NOx/detrusor cGMP levels. The Fructose/Control group showed the compensatory increase of phospho-AKT (Ser473) and phospho-eNOS/eNOS levels, but decreased in eNOS, phospho-eNOS, urinary NOx, and detrusor cGMP levels. CONCLUSION: Our results show dysregulated insulin signalling at bladder mucosa should be a common mechanism of MetS-associated bladder overactivity programmed by pre-and postnatal fructose diet.

Co-design of dementia prevention program for Aboriginal Australians (DAMPAA).

INTRODUCTION: Dementia is highly prevalent in older Aboriginal Australians, with several modifiable risk factors. Currently, there is limited evidence on how to prevent cognitive decline in Aboriginal Australians. METHODS: Based on our Theory of Change (ToC) framework, we co-developed the Dementia risk management and prevention program for Aboriginal Australians (DAMPAA) aged over 45 years in partnership with Aboriginal community-controlled organizations (ACCOs) and Elders. Qualitative data were collected through ACCO staff workshops, Elders yarning, and governance groups to inform the protocol. Additionally, we conducted a small pilot study. RESULTS: Expected DAMPAA ToC outcomes are: (1) improved daily function, (2) better cardiovascular risk management, (3) falls reduction, (4) improved quality of life, and (5) reduced cognitive decline. Attendance enablers are social interaction, environment, exercise type/level, and logistics. DISCUSSION: Findings suggest that ToC is an effective collaborative approach for co-designing Aboriginal health programs.

A brief history of brain iron accumulation in Parkinson disease and related disorders.

Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator.

Milrinone effects on cardiac mitochondria, hemodynamics, and death in catecholamine-infused rats.

BACKGROUND: Catecholamine-storm is considered the major cause of enterovirus 71-associated cardiopulmonary death. To elucidate the effect of milrinone on cardiac mitochondria and death, a rat model of catecholamine-induced heart failure was investigated. METHODS: Young male Spray-Dawley rats received a continuous intravenous infusion of norepinephrine then followed by co-treatment with and without milrinone or esmolol. Vital signs were monitored and echocardiography was performed at indicated time points. At the end of experiments, hearts were extracted to study mitochondrial function, biogenesis, and DNA copy numbers. RESULTS: Hypernorepinephrinemia induced persistent tachycardia, hypertension, and high mortality and significantly impaired the activities of the electron transport chain and suppressed mitochondrial DNA copy number, mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator 1-α. Norepinephrine-induced hypertension could be significantly suppressed by milrinone and esmolol. Milrinone improved but esmolol deteriorated the survival rate. The left ventricle was significantly enlarged shortly after norepinephrine infusion but later gradually reduced in size by milrinone. The impairment and suppression of mitochondrial function could be significantly reversed by milrinone but not by esmolol. CONCLUSIONS: Milrinone may protect the heart via maintaining mitochondrial function from hypernorepinephrinemia. This study warrants the importance of milrinone and the preservation of mitochondrial function in the treatment of catecholamine-induced death. IMPACT: Milrinone may protect the heart from hypernorepinephrinemia-induced death via maintaining myocardial mitochondrial activity, function, and copy number. Maintenance of cardiac mitochondrial function may be a potential therapeutic strategy in such catecholamine-induced heart failure.

NIH Tobacco Research and the Emergence of Tobacco Regulatory Science.

INTRODUCTION: This study explores how the emergence of FDA-funded Tobacco Regulatory Science (TRS) research complements and perhaps influenced the direction of tobacco research supported by NIH. AIMS AND METHODS: New NIH- and FDA-funded tobacco projects awarded in fiscal years (FY) 2011-2020 were identified using internal NIH databases of awarded grants. Project abstracts and research aims were coded by the authors to characterize research domains and tobacco products studied. RESULTS: Between FY 2011 and 2020, NIH funded 1032 and FDA funded 322 new tobacco projects. For the years and grant activity codes studied, the number of new NIH tobacco projects declined while FDA's increased; combined the number of new projects held steady. Much of NIH research included smoking combustibles (43.7%). The most common products in FDA research were cigarettes (74.8%) and e-cigarettes/ENDS (48.1%). Most NIH (58.6%) and FDA (67.7%) projects included research on the determinants of tobacco use. Another area of apparent overlap was health effects (29.5% NIH and 30.1% FDA). Projects unique to NIH included treatment interventions (33.3%), disease pathology/progression (17.8%) and neurobiology (18.9%). A minority of both NIH and FDA projects included populations particularly vulnerable to tobacco product use. CONCLUSIONS: In total, support for new tobacco research supported by NIH and FDA combined remained steady for the time period covered, though there was a concomitant decline in NIH tobacco projects with the increase in FDA-funded TRS projects for the activity codes studied. Despite the apparent overlap in some areas, both NIH and FDA support research that is unique to their respective missions. IMPLICATIONS: NIH continues to support tobacco research that falls within and outside of FDA's regulatory authorities. This research still is needed not only to bolster the evidence base for regulatory decisions at the national and state levels, but also to advance a comprehensive scientific agenda that can inform multiple levels of influence on tobacco control, use and addiction. It will be important to continue monitoring FDA-funded TRS and NIH-funded tobacco research portfolios to ensure that the level of support for and focus of the research is sufficient to address the burden of tobacco-related morbidity and mortality.

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFß, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

The pairs training effect in unfamiliar face matching.

A wealth of studies have shown that humans are remarkably poor at determining whether two face images show the same person or not (face matching). Given the prevalence of photo-ID, and the fact that people employed to check photo-ID are typically unfamiliar with the person pictured, there is a need to improve unfamiliar face matching accuracy. One method of improvement is to have participants complete the task in a pair, which results in subsequent improvements in the low performer ("the pairs training effect"). Here, we sought to replicate the original finding, to test the longevity of the pairs training effect, and to shed light on the potential underlying mechanisms. In two experiments, we replicated the pairs training effect and showed it is maintained after a delay (Experiment 1). We found no differences between high and low performers in confidence (Experiment 1) or response times (Experiment 2), and the content of the pairs' discussions (Experiment 2) did not explain the results. The pairs training effect in unfamiliar face matching is robust, but the mechanisms underlying the effects remain as yet unexplained.

Moving source ocean acoustic tomography with uncertainty quantification using controlled source-tow observations.

Ocean sound speed and its uncertainty are estimated using travel-time tomography at ranges up to 2 km using a moving source in ∼600 m water depth. The experiment included two 32-element vertical line arrays deployed about 1 km apart and a towed source at ∼10 m depth transmitting a linear frequency modulated waveform. The inversion accounts for uncertainties in the positions and velocities of the source and receivers in addition to the background sound speed state. At these short ranges, the sound speed effects are small and the representational error of the candidate forward models must be carefully evaluated and minimized. This is tested stringently by a separate position parameter inversion and by cross-validating the estimates of sound speed and arrival time, including uncertainties. In addition, simulations are used to explore the effects of adding additional constraints to the inversion and to compare the performance of moving to fixed source tomography. The results suggest that the ray diversity available from the moving source reduces the posterior sound speed uncertainty compared to the fixed source case.

Fructose milieu undermines the therapeutic effect of Tribulus terrestris extract on neuroblastoma cell line via maintaining mitochondrial function.

Fructose overconsumption promotes tumor progression. Neuroblastoma is a common extracranial tumor with about 50% 5-year survival rate in high-risk children. The anti-tumor effect of Tribulus terrestris might bring new hope to neuroblastoma therapy. However, whether fructose disturbs the therapeutic effect of T. terrestris is currently unknown. In this study, the mouse neuroblastoma cell line, Neuro 2a (N2a) cells, was used to investigate the therapeutic effects of T. terrestris extract at various dosages (0.01, 1, 100 ng/ml) in regular EMEM medium or extra added fructose (20 mM) for 24 h. 100 ng/ml T. terrestris treatment significantly reduced the cell viability, whereas the cell viabilities were enhanced at the dosages of 0.01 or 1 ng/ml T. terrestris in the fructose milieu instead. The inhibition effect of T. terrestris on N2a migration was blunted in the fructose milieu. Moreover, T. terrestris effectively suppressed mitochondrial functions, including oxygen consumption rates, the activities of electron transport enzymes, the expressions of mitochondrial respiratory enzymes, and mitochondrial membrane potential. These suppressions were reversed in the fructose group. In addition, the T. terrestris-suppressed mitofusin and the T. terrestris-enhance mitochondrial fission 1 protein were maintained at basal levels in the fructose milieu. Together, these results demonstrated that T. terrestris extract effectively suppressed the survival and migration of neuroblastoma via inhibiting mitochondrial oxidative phosphorylation and disturbing mitochondrial dynamics. Whereas, the fructose milieu blunted the therapeutic effect of T. terrestris, particularly, when the dosage is reduced.