Miracle-dz/UniFAR-FTUs huggingface dataset:
KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice

Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund’s adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1–2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.
Riemann problems and dispersive shocks in self-focusing media

The dynamical behavior resulting from an initial discontinuity in focusing media is investigated using a combination of numerical simulations and Whitham modulation theory for the focusing nonlinear Schrodinger equation. Initial conditions with a jump in either or both the amplitude and the local wavenumber are considered. It is shown analytically and numerically that the space-time plane divides into expanding domains in which the solution is described by a slow modulation of genus-zero, genus-one or genus-two solutions, their precise arrangement depending on the specifics of the initial datum
Latent factor in Brain RNA-seq studies reflects cell type and clinical heterogeneity

With the growing availability of Alzheimer’s disease (AD) transcriptomic data, several studies have nominated new therapeutic targets. However, a major challenge is accounting for latent (hidden) factors which affect the discovery of therapeutic targets. Using unsupervised machine learning, we identified a latent factor in brain tissue, and we validated the factor in AD and normal samples, across multiple studies, and different brain tissues. Moreover, significant metabolic differences were observed due to the latent factor. The latent factor was found to reflect cell-type heterogeneity in the brain and after adjusting for it, we were able to identify new biological pathways. The changes observed at both transcriptomic and metabolomic levels support the importance of identifying any latent factors before pursuing downstream analysis to accurately identify biomarkers.
Modular gene interactions drive modular pan-genome evolution in bacteria

Depending on the scale of observation, bacterial genomes are both organized and fluid. While individual bacterial genomes show signatures of organization (e.g., operons), pan-genomes reveal genome fluidity, both in terms of gene content and order (synteny). Here we ask how mutational forces (including recombination and horizontal gene transfer) combine with selection and gene interactions to shape genome organization and variation both within and across strains. We first build an evolutionary simulation model to assess the impact of gene interactions on pan-genome structure. A neutral evolutionary model can produce transient co-segregation of initially linked genes but is vulnerable on longer time-scales to perturbing mutational events. In contrast, incorporation of modular gene fitness interactions can produce sustainable clusters of linked and co-segregating genes, with the network of co-segregation recapitulating the defined simulation ‘ground-truth’ network of gene interactions. To test our model predictions, we exploit the increasing number of closed genomes in model species to define gene co-segregation networks in the pan-genomes of Escherichia coli and Pseudomonas aeruginosa. Using these highly curated pan-genomes, we identify modular clusters of physically linked and co-segregating genes and show that the resulting co-segregation networks map onto underlying gene-regulatory and metabolic gene interaction networks. The results imply that co-segregation networks can contribute to accessory genome annotation, and more generally that gene interactions are the primary force shaping genome structure and operon evolution.
Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age-dependent neuronal loss, and nuclear depletion and cytoplasmic accumulation of TDP-43, accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit while others are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering shared and circuit specific vulnerabilities in ALS/FTD.
Cultivation and Fluorescent in situ hybridization suggest that some shipworm species acquire endosymbiotic bacteria through indirect horizontal transmission

Beneficial microbial symbionts provide essential functions for their host from nutrients to defense against disease. Whether hosts acquire their symbionts directly from parents (vertical transmission) or by sampling from the environment (horizontal transmission) can have dramatic impacts on host adaptability and, in the case of ecosystem engineers, ecosystem health. Wood-boring bivalve mollusks (Teredinidae shipworms) act as ecosystem engineers in marine environments, creating habitat out of submerged wood for fish and invertebrates. Essential to shipworm success is their community of endosymbiotic gill bacteria that produce the enzymes necessary for wood digestion. How shipworms acquire their symbionts, however, remains largely unexplored. Using culturing, fluorescence in-situ hybridization, confocal microscopy, and tank experiments, we provide evidence suggesting the mode of symbiont transmission the shipworms for either the shipworm, Lyrodus pedicellatus or Teredo bartschi or both. Symbiotic bacteria were not detected by cultivation or microscopy in brooding larvae within gravid adults or as veliger larvae collected from the water column, but were observed in adult specimens and juveniles that had begun burrowing into wood. These data suggest that the specimens examined have both aposymbiotic and symbiotic life phases and acquire their symbionts through indirect horizontal transmission. Our findings reveal how the long-term brooders L. pedicellatus and/or T. bartschi acquire their gill endosymbionts. IMPORTANCE How eukaryotic hosts acquire their microbial symbionts can have significant consequences for their ability to adapt to varied environments. Although wood-boring bivalve shipworms have diverse reproductive strategies and are found in unique environments across the globe, little is known about how they transmit their essential gill endosymbionts. We used the closely related shipworms, Lyrodus pedicellatus and/or Teredo bartschi to study how these long-term brooding shipworms acquire their gill endosymbionts. Our work, unlike previous claims for the broadcast spawning species Bankia setacae which reportedly transmits its symbionts directly from parent to offspring, suggests that juvenile L. pedicellatus and/or T. bartschi acquire their symbionts through horizontal transmission rather than directly from their parents. This work reveals the mechanism by which some brooding shipworm species acquire their symbionts, adding to our limited understanding of intracellular symbiont transmission of Teredinidae.
Control of cell proliferation by memories of mitosis

Mitotic duration is tightly constrained, with extended mitotic duration being a characteristic of potentially problematic cells prone to chromosome missegregation and genomic instability. We show that memories of mitotic duration are integrated by a p53-based mitotic stopwatch pathway to exert tight control over proliferation. The stopwatch halts proliferation of the products of a single significantly extended mitosis or of successive modestly extended mitoses. Time in mitosis is monitored via mitotic kinase-regulated assembly of stopwatch complexes that are transmitted to daughter cells. The stopwatch is inactivated in p53-mutant cancers, as well as in a significant proportion of p53-wildtype cancers, consistent with classification of stopwatch complex subunits as tumor suppressors. Stopwatch status additionally influences efficacy of anti-mitotic agents currently used or in development for cancer therapy. One-Sentence Summary Time spent in mitosis is carefully monitored to halt the proliferation of potentially dangerous cells in a population.
The moduli space of three-qutrit states

We study the invariant theory of trilinear forms over a three-dimensional complex vector space, and apply it to investigate the behavior of pure entangled three-partite qutrit states and their normal forms under local filtering operations (SLOCC). We describe the orbit space of the SLOCC group SL(3,C)×3 both in its affine and projective versions in terms of a very symmetric normal form parametrized by three complex numbers. The parameters of the possible normal forms of a given state are roots of an algebraic equation, which is proved to be solvable by radicals. The structure of the sets of equivalent normal forms is related to the geometry of certain regular complex polytopes.
Tidal Decay of Circumbinary Planetary Systems

It is shown that circumbinary planetary systems are subject to universal tidal decay (shrinkage of orbits), caused by the forced orbital eccentricity inherent to them. Circumbinary planets (CBPs) are liberated from parent systems when, owing to the shrinkage, they enter the circumbinary chaotic zone. On shorter timescales (less than the current age of the universe), the effect may explain, at least partially, the observed lack of CBPs of close-enough (with periods <5 days) stellar binaries; on longer timescales (greater than the age of the universe but well within stellar lifetimes), it may provide massive liberation of chemically evolved CBPs. Observational signatures of the effect may comprise (1) a prevalence of large rocky planets (super-Earths) in the whole population of rogue planets (if this mechanism were the only source of rogue planets); (2) a mass-dependent paucity of CBPs in systems of low-mass binaries: the lower the stellar mass, the greater the paucity.
Three-dimensional Simulations of the Chemical and Dynamical Evolution of the Galactic Bulge

A three-dimensional, hydrodynamical, N-body model for the formation of the Galaxy is presented, with special attention paid to the formation of the bulge component. Since none of the previous numerical models for the Galaxy's formation have a proper treatment of the chemical evolution and/or sufficient spatial resolutions, we have constructed a detailed model of the chemical and dynamical evolution of the Galaxy using our GRAPE smoothed particle hydrodynamics (SPH) code. Our SPH code includes various physical processes related to the formation of stellar systems. Starting with cosmologically motivated initial conditions, we obtain a stellar system qualitatively similar to the Galaxy. Then we analyze the chemical and kinematic properties of the bulge stars in our model and find qualitative agreement with observational data. The early evolution of our model has revealed that most bulge stars form during the subgalactic merger (merger component of the bulge stars). Because of the strong starburst induced by the merger, the metallicity distribution function of such stars becomes as wide as observed. We find that another group of the bulge stars forms later in the inner region of the disk (nonmerger component of the bulge stars). Because of the difference in the formation epoch, the main source of iron for this group of stars is different from that for the merger component. Iron in the merger and nonmerger components comes mainly from Type II and Type Ia supernovae, respectively. Since a Type Ia supernova ejects ~10 times more iron than a Type II supernova, [Fe/H] of the nonmerger component tends to be higher than that of the merger component, which widens the metallicity distribution function. From these results, we suggest that the Galactic bulge consists of two chemically different components; one has formed quickly through the subgalactic clump merger in the proto-Galaxy, and the other has formed gradually in the inner disk.
Nonlinear Tempering of Subdiffusion with Chemotaxis, Volume Filling, and Adhesion

The purpose of this paper is to implement nonlinear particle interactions into subdiffusive transport, involving chemotaxis and nonlinear effects such as volume filling and adhesion. We systematically derive nonlinear subdiffusive fractional equations with chemoattractant dependent forcing. We consider the diffusion limit of the master equation and analyse the role of nonlinear tempering in the stationary case. We study the interaction between attractive forces of anomalous aggregation and chemotaxis, with repulsive forces induced by nonlinear reactions. We show that this nonlinear interaction can prevent the phenomenon of anomalous aggregation when the local particle concentration grows too high. We also show that the effect of nonlinear tempering is to suppress the intermediate subdiffusive behaviour which results in a nonlinear advection diffusion equation in the long time limit.
Spectra and Bifurcations

The concept of spectrum for a class of non-linear wave equations is studied. Instead of looking for stability, the key to the spectral structure is found in the instability phenomena (bifurcations). This aspect is best seen in the `classical model' of the non-linear wave mechanics. The solitons (macro-localizations) are a part of the non-linear spectral problem; their bifurcations reflect the dynamical symmetry breaking. The computer simulations suggest that the bifurcations of the asymptotic behaviour occur also for the general, non-stationary states. A~phenomenon of the soliton splitting is observed.
Estimating the transition of individuals between life stages

Over their lifetimes, individuals of a species transition from one stage of their life cycle to the next (for example, a nonreproductive juvenile will mature to a reproductive adult). Estimating the age at which these transitions occur can be complex for a variety of reasons. A fundamental, generalizable way to assess the mean age of transition along with a standard deviation of the distribution of the transition is developed. We propose and statistically develop a method that is easy to use, requires only one data collection period, and provides reliable estimates for the mean and the standard deviation of the transition point. Our results for the case studies for one species, Carnegiea gigantea, using eight independent real‐world datasets, are robust, confirming the validity and usefulness of the proposed technique. We develop an important ecological metric that quantifies the age at which a species transitions from one stage to another in its life cycle. This is a basic ecological metric that is often assumed, but that until now has been difficult to quantify practically for many species. This metric is easy to use (we provide a spreadsheet that does all the calculations) and essential for all life scientists, regardless of species, life form, or ecosystem of study. Copyright © 2015 John Wiley & Sons, Ltd.
Particle acceleration in the Herbig–Haro objects HH 80 and HH 81

We present an analysis of radio (Karl G. Jansky Very Large Array (VLA)), optical (HST), and X-ray (Chandra and XMM-Newton) observations and archival data of the Herbig-Haro objects HH 80 and HH 81 in the context of jet-cloud interactions. Our radio images are the highest angular resolution to date of these objects, allowing to spatially resolve the knots and compare the regions emitting in the different spectral ranges. We found that soft X-ray thermal emission is located ahead of the non-thermal radio peak. This result is consistent with a radiative forward shock that heats the shocked gas up to 10 6 K, and an adiabatic reverse shock able to accelerate particles and produce synchrotron radiation detectable at radio frequencies. These high angular resolution radio images also reveal a bow shock structure in the case of HH 80N, being the first time this morphology is detected in a Herbig-Haro object at these frequencies.
Circumnuclear Multiphase Gas in Circinus Galaxy. III. Structure of the Nuclear Ionized Gas

We investigate the properties of the ionized gas irradiated by an active galactic nucleus (AGN) based on our “radiation-driven fountain” model for the nearest type-2 Seyfert galaxy, the Circinus galaxy. We conducted “quasi-three-dimensional” spectral analysis using the spectral synthesis code Cloudy and obtained the surface brightness distributions of lines, such as Hα, Hβ, [O iii], [N ii], and [S ii] for the central 16 pc region. The ionized regions observed based on these lines show a conical morphology around the rotation axis, even if we do not phenomenologically postulate the presence of an optically thick “torus. ” This region also shows non-uniform internal structures, reflecting the inhomogeneous structure of fountain flows. Using ionization diagnostic diagrams, we investigated the spectral properties of the ionized gas. The diagrams based on the line ratios of [N ii]/Hα and [S ii]/Hα show that most regions of the cone have the same properties as those in the narrow line regions (NLRs) in AGNs, whereas using [O i]/Hα, the central 10 pc regions are rather LINER-like. The gas density, temperature, and ionizing parameter in regions identified as “NLR” are typically n ∼ 300–1500 cm−3, T ∼ (1–3) × 104 K, and U ∼ 0.01, respectively. The morphology and [O iii] intensity are similar to the base of the observed [O iii] cone in the Circinus galaxy, implying some physical connections with the origin of the ∼100 pc scale NLR.
A New Method to Measure Star Formation Rates in Active Galaxies Using Mid-infrared Neon Emission Lines

The star formation rate (SFR) is one of the most fundamental parameters of galaxies, but nearly all of the standard SFR diagnostics are difficult to measure in active galaxies because of contamination from the active galactic nucleus (AGN). Being less sensitive to dust extinction, the mid-infrared fine-structure lines of [Ne ii] 12.81 μm and [Ne iii] 15.56 μm effectively trace the SFR in star-forming galaxies. These lines also have the potential to serve as a reliable SFR indicator in active galaxies, provided that their contribution from the AGN narrow-line region (NLR) can be removed. We use a new set of photoionization calculations with realistic AGN spectral energy distributions and input assumptions to constrain the magnitude of [Ne ii] and [Ne iii] produced by the NLR for a given strength of [Ne v] 14.32 μm. We demonstrate that AGNs emit a relatively restricted range of [Ne ii]/[Ne v] and [Ne iii]/[Ne v] ratios. Hence, once [Ne v] is measured,the AGN contribution to the low-ionization Ne lines can be estimated, and the SFR can be determined from the strength of [Ne ii] and [Ne iii]. We find that AGN host galaxies have similar properties as compact extragalactic H ii regions, which indicates that the star formation in AGN hosts is spatially concentrated. This suggests a close relationship between black hole accretion and nuclear star formation. We update the calibration of [Ne ii] and [Ne iii] strength as an SFR indicator, explicitly considering the effects of metallicity, finding very good relations between Ne fractional abundances and the [Ne iii]/[Ne ii] ratio for different metallicities, ionization parameters, and starburst ages. Comparison of neon-based SFRs with independent SFRs for active and star-forming galaxies shows excellent consistency with small scatter (∼0.18 dex).
Differential scattering cross sections for elements with 13 ⩽ Z ⩽ 50 using 59.54 keV gamma rays

Coherent and incoherent scattering cross sections have been measured using a high purity germanium detector on elements in the range of Z = 13–50 using 241Am gamma rays. The cross sections have been derived by comparing the net count rate obtained from the Compton peak of aluminum with the elastic/Compton peak of the target element. The measured cross sections for the coherent and incoherent processes are in agreement with the theoretical values.
Lightly Bound Skyrmions, Tetrahedra and Magic Numbers

In the lightly bound Skyrme model, several Skyrmions having particularly strong binding are clusters of unit baryon number Skyrmions arranged as truncated tetrahedra. Their baryon numbers form the sequence B = 4, 16, 40, 80, 140, 224. This is the standard sequence of tetrahedral numbers multiplied by four, and therefore agrees with the sequence of magic proton and neutron numbers 2, 8, 20, 40, 70, 112 that occurs in the nuclear shell model in the absence of strong spin-orbit coupling. This sequence includes several of the magic numbers that are predicted for tetrahedrally deformed nuclei, and also appears in the context of the FCC lattice geometry investigated long ago by Wigner and revived more recently.