Toward Powerful Probes of Neutrino Self-Interactions in Supernovae.

Neutrinos remain mysterious. As an example, enhanced self-interactions (νSI), which would have broad implications, are allowed. At the high neutrino densities within core-collapse supernovae, νSI should be important, but robust observables have been lacking. We show that νSI make neutrinos form a tightly coupled fluid that expands under relativistic hydrodynamics. The outflow becomes either a burst or a steady-state wind; which occurs here is uncertain. Though the diffusive environment where neutrinos are produced may make a wind more likely, further work is needed to determine when each case is realized. In the burst-outflow case, νSI increase the duration of the neutrino signal, and even a simple analysis of SN 1987A data has powerful sensitivity. For the wind-outflow case, we outline several promising ideas that may lead to new observables. Combined, these results are important steps toward solving the 35-year-old puzzle of how νSI affect supernovae.

The origin of the elements: a century of progress.

This review assesses the current state of knowledge of how the elements were produced in the Big Bang, in stellar lives and deaths, and by interactions in interstellar gas. We begin with statements of fact and discuss the evidence that convinced astronomers that the Sun is fusing hydrogen, that low-mass stars produce heavy elements through neutron capture, that massive stars can explode as supernovae and that supernovae of all types produce new elements. Nucleosynthesis in the Big Bang, through cosmic ray spallation, and in exploding white dwarfs is only ranked below the above facts in certainty because the evidence, while overwhelming, is so far circumstantial. Next, we highlight the flaws in our current understanding of the predictions for lithium production in the Big Bang and/or its destruction in stars and for the production of the elements with atomic number [Formula: see text]. While the theory that neutron star mergers produce elements through neutron-capture has powerful circumstantial evidence, we are unconvinced that they produce all of the elements past nickel. Also in dispute is the exact mechanism or mechanisms that cause the white dwarfs to explode. It is difficult to determine the origin of rare isotopes because signatures of their production are weak. We are uncertain about the production sites of some lithium and nitrogen isotopes and proton-rich heavy nuclei. Finally, Betelgeuse is probably not the next star to become a supernovae in the Milky Way, in part because Betelgeuse may collapse directly to a black hole instead. The accumulated evidence in this review shows that we understand the major production sites for the elements, but islands of uncertainty in the periodic table exist. Resolving these uncertainties requires in particular understanding explosive events with compact objects and understanding the nature of the first stars and is therefore primed for new discoveries in the next decades. This article is part of the theme issue 'Mendeleev and the periodic table'.

Intensive Working Memory Training Produces Functional Changes in Large-scale Frontoparietal Networks.

Working memory is central to human cognition, and intensive cognitive training has been shown to expand working memory capacity in a given domain. It remains unknown, however, how the neural systems that support working memory are altered through intensive training to enable the expansion of working memory capacity. We used fMRI to measure plasticity in activations associated with complex working memory before and after 20 days of training. Healthy young adults were randomly assigned to train on either a dual n-back working memory task or a demanding visuospatial attention task. Training resulted in substantial and task-specific expansion of dual n-back abilities accompanied by changes in the relationship between working memory load and activation. Training differentially affected activations in two large-scale frontoparietal networks thought to underlie working memory: the executive control network and the dorsal attention network. Activations in both networks linearly scaled with working memory load before training, but training dissociated the role of the two networks and eliminated this relationship in the executive control network. Load-dependent functional connectivity both within and between these two networks increased following training, and the magnitudes of increased connectivity were positively correlated with improvements in task performance. These results provide insight into the adaptive neural systems that underlie large gains in working memory capacity through training.

Roles of default-mode network and supplementary motor area in human vigilance performance: evidence from real-time fMRI.

We used real-time functional magnetic resonance imaging (fMRI) to determine which regions of the human brain have a role in vigilance as measured by reaction time (RT) to variably timed stimuli. We first identified brain regions where activation before stimulus presentation predicted RT. Slower RT was preceded by greater activation in the default-mode network, including lateral parietal, precuneus, and medial prefrontal cortices; faster RT was preceded by greater activation in the supplementary motor area (SMA). We examined the roles of these brain regions in vigilance by triggering trials based on brain states defined by blood oxygenation level-dependent activation measured using real-time fMRI. When activation of relevant neural systems indicated either a good brain state (increased activation of SMA) or a bad brain state (increased activation of lateral parietal cortex and precuneus) for performance, a target was presented and RT was measured. RTs on trials triggered by a good brain state were significantly faster than RTs on trials triggered by a bad brain state. Thus human performance was controlled by monitoring brain states that indicated high or low vigilance. These findings identify neural systems that have a role in vigilance and provide direct evidence that the default-mode network has a role in human performance. The ability to control and enhance human behavior based on brain state may have broad implications.

Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways.

Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models. TQ, bifunctionally, activates both aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Genetic deletion studies reveal that TQ-induced AhR activation transcriptionally increases CLDN3 via xenobiotic response element (XRE) in the CLDN3 promoter. Conversely, TQ suppresses CLDN2 expression via Nrf2-mediated STAT3 inhibition. TQ offers a naturally occurring, non-toxic intervention for enhancement of the intestinal TJ barrier and adjunct therapeutics to treat intestinal inflammation.

When the brain is prepared to learn: enhancing human learning using real-time fMRI.

The rate of learning or memory formation varies over time for any individual, partly due to moment-to-moment fluctuation of brain state. Functional neuroimaging has revealed the neural correlates of learning and memory, but here we asked if neuroimaging can causally enhance human learning by detection of brain states that reveal when a person is prepared or not prepared to learn. The parahippocampal cortex (PHC) is essential for memory formation for scenes. Here, activation in PHC was monitored in real-time, and scene presentations were triggered when participants entered "good" or "bad" brain states for learning of novel scenes. Subsequent recognition memory was more accurate for scenes presented in "good" than "bad" brain states. These findings show that neuroimaging can identify in real-time brain states that enhance or depress learning and memory formation, and knowledge about such brain states may be useful for accelerating education and training. Further, the use of functional neuroimaging as a causal, rather than correlative, tool to study the human brain may open new insights into the neural basis of human cognition.

The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells.

BACKGROUND: The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down-regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down-regulates AR expression in several prostate cancer cell lines. METHODS: ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4-2, and LAPC-4 prostate cancer cells. RESULTS: ca27 induced the down-regulation of AR protein expression in LNCaP, C4-2, and LAPC-4 cells within 12 hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF-E2-related factor 2 (Nrf2) and the induction of the Nrf2-regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27-mediated down-regulation of the AR was attenuated by the antioxidant, N-acetyl cysteine. CONCLUSIONS: ca27 induces ROS and mediates AR protein down-regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down-regulation, which could lead to effective new anti-androgenic strategies for the treatment of advanced prostate cancer.

Preferences for pharmacogenomic testing in polypharmacy patients: a discrete choice experiment.

Aim: To elicit preferences for pharmacogenomic (PGx) testing in polypharmacy patients. Materials & methods: A face-to-face discrete choice experiment survey was designed and administered to adult polypharmacy patients recruited at a local retail pharmacy in Albuquerque (NM, USA). Results: A total of 128 eligible polypharmacy patients completed the discrete choice experiment survey and significantly preferred a PGx test with lower cost, better confidentiality and higher certainty of identifying best medication/dose and side effects and one that can be used to advocate for their treatment needs (all p < 0.01). Conclusion: This is the first study eliciting preferences for PGx testing among polypharmacy patients. The study found most polypharmacy patients were willing to take a PGx test and their preferences were mostly influenced by test cost.

Patients who concurrently take five or more medications are at a higher risk of experiencing side effects related to drug­drug/drug­gene interactions. 'One size doesn't fit all' ­ individuals may respond differently to the same dose of a medication. Pharmacogenomic (PGx) testing identifies individual genetic information that may help explain better or worse outcomes or potential problems with drug therapies and eventually may help optimize patient treatment. The authors conducted a face-to-face survey to assess preferences for PGx testing in polypharmacy patients and found that most polypharmacy patients were willing to take a PGx test and their preferences were mostly influenced by test cost and performance, as well as the confidentiality of test results.

Blinding efficacy and adverse events following repeated transcranial alternating current, direct current, and random noise stimulation.

As transcranial electrical stimulation (tES) protocols advance, assumptions underlying the technique need to be retested to ensure they still hold. Whilst the safety of stimulation has been demonstrated mainly for a small number of sessions, and small sample size, adverse events (AEs) following multiple sessions remain largely untested. Similarly, whilst blinding procedures are typically assumed to be effective, the effect of multiple stimulation sessions on the efficacy of blinding procedures also remains under question. This is especially relevant in multisite projects where small unintentional variations in protocol could lead to inter-site difference. We report AE and blinding data from 1,019 participants who received up to 11 semi-consecutive sessions of active or sham transcranial alternating current stimulation (tACS), direct current stimulation (tDCS), and random noise stimulation (tRNS), at 4 sites in the UK and US. We found that AEs were often best predicted by factors other than tES, such as testing site or session number. Results from the blinding analysis suggested that blinding was less effective for tDCS and tACS than tRNS. The occurrence of AEs did not appear to be linked to tES despite the use of smaller electrodes or repeated delivery. However, blinding efficacy was impacted in tES conditions with higher cutaneous sensation, highlighting a need for alternative stimulation blinding protocols. This may be increasingly necessary in studies wishing to deliver stimulation with higher intensities.

Computing moment-to-moment BOLD activation for real-time neurofeedback.

Estimating moment-to-moment changes in blood oxygenation level dependent (BOLD) activation levels from functional magnetic resonance imaging (fMRI) data has applications for learned regulation of regional activation, brain state monitoring, and brain-machine interfaces. In each of these contexts, accurate estimation of the BOLD signal in as little time as possible is desired. This is a challenging problem due to the low signal-to-noise ratio of fMRI data. Previous methods for real-time fMRI analysis have either sacrificed the ability to compute moment-to-moment activation changes by averaging several acquisitions into a single activation estimate or have sacrificed accuracy by failing to account for prominent sources of noise in the fMRI signal. Here we present a new method for computing the amount of activation present in a single fMRI acquisition that separates moment-to-moment changes in the fMRI signal intensity attributable to neural sources from those due to noise, resulting in a feedback signal more reflective of neural activation. This method computes an incremental general linear model fit to the fMRI time series, which is used to calculate the expected signal intensity at each new acquisition. The difference between the measured intensity and the expected intensity is scaled by the variance of the estimator in order to transform this residual difference into a statistic. Both synthetic and real data were used to validate this method and compare it to the only other published real-time fMRI method.

Drug Repurposing from an Academic Perspective.

Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members.

Autophagy is a cellular degradative process that has multiple important actions in cancer. Autophagy modulation is under consideration as a promising new approach to cancer therapy. However, complete autophagy dysregulation is likely to have substantial undesirable side effects. Thus, more targeted approaches to autophagy modulation may prove clinically beneficial. One potential avenue to achieving this goal is to focus on the actions of tripartite motif-containing protein family members (TRIMs). TRIMs have key roles in an array of cellular processes, and their dysregulation has been extensively linked to cancer risk and prognosis. As detailed here, emerging data shows that TRIMs can play important yet context-dependent roles in controlling autophagy and in the selective targeting of autophagic substrates. This review covers how the autophagy-related actions of TRIM proteins contribute to cancer and the possibility of targeting TRIM-directed autophagy in cancer therapy.

Acute social isolation evokes midbrain craving responses similar to hunger.

When people are forced to be isolated from each other, do they crave social interactions? To address this question, we used functional magnetic resonance imaging to measure neural responses evoked by food and social cues after participants (n = 40) experienced 10 h of mandated fasting or total social isolation. After isolation, people felt lonely and craved social interaction. Midbrain regions showed selective activation to food cues after fasting and to social cues after isolation; these responses were correlated with self-reported craving. By contrast, striatal and cortical regions differentiated between craving food and craving social interaction. Across deprivation sessions, we found that deprivation narrows and focuses the brain's motivational responses to the deprived target. Our results support the intuitive idea that acute isolation causes social craving, similar to the way fasting causes hunger.

Response to Comment on "A noninteracting low-mass black hole-giant star binary system".

Van den Heuvel and Tauris argue that if the red giant star in the system 2MASS J05215658+4359220 has a mass of 1 solar mass (M ☉), then its unseen companion could be a binary composed of two 0.9 M ☉ stars, making a triple system. We contend that the existing data are most consistent with a giant of mass [Formula: see text] M ☉, implying a black hole companion of [Formula: see text] M ☉.

Detection of intracellular granularity induction in prostate cancer cell lines by small molecules using the HyperCyt high-throughput flow cytometry system.

Prostate cancer is a leading cause of death among men due to the limited number of treatment strategies available for advanced disease. Discovery of effective chemotherapeutics involves the identification of agents that inhibit cancer cell growth. Increases in intracellular granularity have been observed during physiological processes that include senescence, apoptosis, and autophagy, making this phenotypic change a useful marker for identifying small molecules that induce cellular growth arrest or death. In this regard, epithelial-derived cancer cell lines appear uniquely susceptible to increased intracellular granularity following exposure to chemotherapeutics. We have established a novel flow cytometry approach that detects increases in side light scatter in response to morphological changes associated with intracellular granularity in the androgen-sensitive LNCaP and androgen-independent PC3 human prostate cancer cell lines. A cell-based assay was developed to screen for small molecule inducers of intracellular granularity using the HyperCyt high-throughput flow cytometry platform. Validation was performed using the Prestwick Chemical Library, where known modulators of LNCaP intracellular granularity, such as testosterone, were identified. Nonandrogenic inducers of granularity were also detected. A further screen of approximately 25,000 small molecules led to the identification of a class of aryl-oxazoles that increased intracellular granularity in both cell lines, often leading to cell death. The most potent agents exhibited submicromolar efficacy in LNCaP and PC3 cells.

A noninteracting low-mass black hole-giant star binary system.

Black hole binary systems with companion stars are typically found via their x-ray emission, generated by interaction and accretion. Noninteracting binaries are expected to be plentiful in the Galaxy but must be observed using other methods. We combine radial velocity and photometric variability data to show that the bright, rapidly rotating giant star 2MASS J05215658+4359220 is in a binary system with a massive unseen companion. The system has an orbital period of ~83 days and near-zero eccentricity. The photometric variability period of the giant is consistent with the orbital period, indicating star spots and tidal synchronization. Constraints on the giant's mass and radius imply that the unseen companion is [Formula: see text] solar masses, indicating that it is a noninteracting low-mass black hole or an unexpectedly massive neutron star.

A multifunctional androgen receptor screening assay using the high-throughput Hypercyt flow cytometry system.

The androgen receptor (AR) is a steroid hormone receptor which regulates transcription of androgen-sensitive genes and is responsible for the development and maintenance of male secondary sexual characteristics. Chemicals that interfere with AR activity may lead to pathological conditions in androgen-sensitive tissues. A variety of reporter systems have been developed, driven by androgen-sensitive promoters, which screen for chemicals that modulate androgenic activity. We have developed a flexible, high-throughput AR transcriptional activation assay, designated the Multifunctional Androgen Receptor Screening (MARS) assay, to facilitate the identification of novel modulators of AR transcriptional activity using flow cytometry. Androgen-independent human prostate cancer-derived PC3 cells were transiently cotransfected with an expression vector for the wild-type human AR and an androgen-sensitive promoter regulating the expression of destabilized enhanced GFP (dsEGFP). The transfected cells were stimulated with established androgenic and antiandrogenic compounds and assessed for increased or decreased dsEGFP expression. To screen for antagonists of AR transcription, the AR agonist R1881 was coadministered at submaximal concentrations with potential AR antagonists. The assay was formatted for high-throughput screening using the HyperCyt flow cytometry system. Agents with established androgenic and antiandrogenic activity were used for validation of the MARS assay. AR agonists were found to potently induce dsEGFP. Furthermore, AR agonists induced dsEGFP expression in a dose-dependent manner. Alternatively, AR antagonists blocked dsEGFP expression when coadministered with low-dose R1881, which also occurred in a dose-dependent manner. Modulators of AR transcriptional activity can be successfully identified by the MARS assay, utilizing a rapid, flexible, sensitive, and high-throughput format. Dose-response curves can be successfully generated for these compounds, allowing for an assessment of potency. Because of its simplicity and high-throughput compatibility, the MARS assay and HyperCyt system combined with flow cytometric analysis represents a valuable and novel addition to the current repertoire of AR transcriptional activation screening assays.

A test of rats' tolerance for 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK), a new anti-androgen.

Following the demonstration that the androgen activity of androsta-5-ene-3beta,17beta-diol (Adiol) is not inhibited by the anti-androgens currently used to treat prostate cancer, we sought agents that would inhibit the androgenic function of Adiol as well as of dihydrotestosterone. The steroid 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK) met this criterion. Its tolerance was assessed in rats by oral and by subcutaneous administration for four weeks. Neither route of ADEK administration resulted in any behavioral changes. There was no effect on weight gain during the 28 days of steroid intake and no effect on the weight of the kidneys, heart, liver, testes, adrenals or the ventral lobe of the prostate glands. The seminal vesicles of the treated rats were 23-29% and the weights of the anterior prostates of the respective groups were 17-26% smaller than the controls. In contrast, the dorsolateral prostates were increased 26-55% as compared with the controls. There were no detectable changes in the histology of the kidneys, hearts, livers, testes and adrenals of any of the rats, but both groups of ADEK-treated rats had mild atrophic changes in their seminal vesicles and in the ventral lobe of their prostate glands. Both ADEK-treated groups showed focal glandular epithelial hyperplasia in the dorsolateral lobes in comparison with the control group. Orally administered ADEK was rapidly converted to several metabolites, which were nearly completely cleared from the blood within 4h.

Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.

Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.