Biological and clinical significance of cancer stem cell plasticity

In the past decade, the traditional view of cancers as a homogeneous collection of malignant cells is being replaced by a model of ever increasing complexity suggesting that cancers are complex tissues composed of multiple cell types. This complex model of tumorigenesis has been well supported by a growing body of evidence indicating that most cancers including those derived from blood and solid tissues display a hierarchical organization of tumor cells with phenotypic and functional heterogeneity and at the apex of this hierarchy are cells capable of self‐renewal. These “tumor imitating cells” or “cancer stem cells” drive tumorigenesis and contribute to metastasis, treatment resistance and tumor relapse. Although tumor stem cells themselves may display both genetic and phenotypic heterogeneity, recent studies have demonstrated that cancer stem cells maintain plasticity to transition between mesenchymal‐like (EMT) and epithelial‐like (MET) states, which may be regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in tumor progression and treatment resistance. In this review, we discuss the emerging knowledge regarding the plasticity of cancer stem cells with an emphasis on the signaling pathways and noncoding RNAs including microRNAs (miRNA) and long non‐coding RNAs (lncRNAs) in regulation of this plasticity during tumor growth and metastasis. Lastly, we point out the importance of targeting both the EMT and MET states of CSCs in order to eliminate these lethal seeds of cancers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155480/1/ctm2s4016901400323.pd

Extending the Discovery Potential for Inelastic-Dipole Dark Matter with FASER

Neutral particles are notoriously difficult to observe through electromagnetic interactions. As a result, they naturally elude detection in most collider detectors. In this paper, we point out that neutral particles that interact through a dipole interaction can nevertheless be detected in far-forward detectors designed to search for long-lived particles (LLPs). In contrast to previous analyses that focused on neutral particles with elastic interactions, we consider inelastic interactions. This naturally leads to LLPs, and we demonstrate that FASER (and future experiments at the Forward Physics Facility) will be able to probe substantial regions of the associated parameter space. In particular, we find that FASER is capable of probing the region of parameter space wherein thermal freeze-out gives rise to an $\mathcal{O}$(GeV) dark-matter candidate with the appropriate relic abundance, as well as regions of parameter space that are difficult to probe at fixed-target experiments. FASER and its successor experiments may therefore play a critical role in the discovery of such a dark-matter candidate.Comment: 24 pages, LaTeX, 5 figures, 1 tabl

Alzheimer’s Disease (AD) Detect & Prevent: presymptomatic AD detection and prevention

Alzheimer’s disease (AD) is a major cause of the rapidly growing and crushing aging challenge that threatens to economically undermine today’s healthcare system. AD prevalence will grow to over 100 million cases in 2050. AD is incurable but can be prevented. Therefore, the most viable solution may be to detect very early signs of AD (presymptomatically) in citizens-at-risk and to intervene in time to reduce AD risk or prevent it entirely. The present project will refine and validate two breakthrough innovations for AD detection and AD prevention and commercialize them as a one-stop digital medical device, named ‘AD Detect & Prevent’. The first innovation is a highly sensitive cognitive assessment method recently pioneered by a group of researchers that has been shown to detect subtle presymptomatic stage cognitive decline specific to AD. This will be integrated with the second innovation – a digital AD prevention programme delivered on an award-winning computerized cognitive training and rehabilitation platform (app + web) that uses high intensity immersive and adaptive ‘neurogames’ and audio-based therapy for behavioural intervention, designed for strengthening core cognitive functions, building cognitive reserve, changing lifestyle and thus reducing the overall AD risk in individuals. The detection and prevention methods will undergo vigorous scientific validation, and the ambition is to create and become the global standard of care for precise presymptomatic detection of AD and effective AD prevention

The nature of H I absorbers in gamma-ray burst afterglows: clues from hydrodynamic simulations

In recent work, we have shown that it is possible to link quantitatively many aspects of damped Lyman α (DLA) absorbers in the spectra of quasars to high-resolution simulations of galaxy formation. Using runs from the same series of hydrodynamic numerical studies, we consider the expected properties of intrinsic Lyman α absorbers seen in the spectra of high-redshift (z > 2) gamma-ray burst afterglows (GRB–DLAs). If GRBs are associated with the death of massive stars, their afterglows provide insights into otherwise unprobed regions of protogalactic objects, but detailed physical interpretations are currently embryonic. We find that median impact parameters (measured from the potential minimum) are approximately 1 kpc for GRBs compared with 4 kpc for quasi-stellar object–DLA (QSO–DLA). However, an equally important difference is that GRB–DLAs are predominantly associated with haloes of mass 10^(10) < M_(vir)/M_⊙ < 10^(12) , an order of magnitude larger than the hosts of QSO–DLAs. Accordingly, there are differences in the stellar properties of hosts. For instance, mean star formation rates are higher: <M(overdot)_★ ≃ 10 M_⊙ yr^(-1) for GRB–DLAs compared with <M(overdot)_★ ≃ 1 M_⊙ yr^(-1) for QSO–DLAs. Our simulations accurately predict the form of the GRB–DLA H I column density distribution, producing quantitative agreement for N_(H I) > 10^(19) cm^(−2) , but they somewhat underpredict the incidence of low column densities N_(H I_ < 10^(19) cm^(−2) . This is reflected in our estimate of the ionizing photon escape fraction, f_(esc) ≃ 1 per cent, which is lower than the observational GRB-derived escape fraction (2 per cent). Line-of-sight neutral gas metallicities predicted by our simulations (10^(−2) < Z/Z_⊙ < 1) are consistent with the modest observational constraints. Because of large internal dispersions in gas metallicities, this agreement is not significantly compromised by imposing a cut-off on the metallicity of stars able to launch GRBs (Z_★ < Z_⊙/3) , confounding claims that the observed metallicity of GRB–DLAs poses a severe challenge to current GRB models

Orbital, charge, and spin couplings in Ru 25+O9 dimers of Ba3CoRu2O9

e magnetic, transport, and structural properties of cold-pressed Ba3CoRu2O9 show (i) an antiferromagnetic transition, (ii) a semiconductor-semiconductor electronic transition where the resistivity is dominated by the electron hopping between the Ru25+O9 dimers with itinerant Ru electrons at high temperatures, and (iii) a hexagonal to orthorhombic structural phase transition. All three transitions occur at 93 K and are related to the Ru5+ ions in the Ru2O9 dimers. The Ru-O bond distortion below 93 K further indicates a possible orbital ordering for Ru5+ ions in isolated Ru2O9 dimers, which accounts for the strong orbital, charge, and spin couplingsThis work is supported by NSF-DMR-0654118 and the State of Florida. J.S.B. and A.K. acknowledge support from NSF-DMR-1005293S

Large scale outflows from z ~ 0.7 starburst galaxies identified via ultra-strong MgII quasar absorption lines

(Abridged) Star formation-driven outflows are a critical phenomenon in theoretical treatments of galaxy evolution, despite the limited ability of observations to trace them across cosmological timescales. If the strongest MgII absorption-line systems detected in the spectra of background quasars arise in such outflows, "ultra-strong" MgII (USMgII) absorbers would identify significant numbers of galactic winds over a huge baseline in cosmic time, in a manner independent of the luminous properties of the galaxy. To this end, we present the first detailed imaging and spectroscopic study of the fields of two USMgII absorber systems culled from a statistical absorber catalog, with the goal of understanding the physical processes leading to the large velocity spreads that define such systems. Each field contains two bright emission-line galaxies at similar redshift (dv < 300 km/s) to that of the absorption. Lower-limits on their instantaneous star formation rates (SFR) from the observed OII and Hb line fluxes, and stellar masses from spectral template fitting indicate specific SFRs among the highest for their masses at z~0.7. Additionally, their 4000A break and Balmer absorption strengths imply they have undergone recent (~0.01 - 1 Gyr) starbursts. The concomitant presence of two rare phenomena - starbursts and USMgII absorbers - strongly implies a causal connection. We consider these data and USMgII absorbers in general in the context of various popular models, and conclude that galactic outflows are generally necessary to account for the velocity extent of the absorption. We favour starburst driven outflows over tidally-stripped gas from a major interaction which triggered the starburst as the energy source for the majority of systems. Finally, we discuss the implications of these results and speculate on the overall contribution of such systems to the global SFR density at z~0.7.Comment: 15 pages, 6 figure, accepted for publication by MNRA

The Structure and Kinematics of the Circum-Galactic Medium from Far-UV Spectra of z~2-3 Galaxies

We present new results on the kinematics and spatial distribution of metal-enriched gas within 125 kpc (physical) of Lyman Break galaxies at redshifts z~2-3. In particular, we demonstrate how rest-UV galaxy spectra can be used to obtain key spatial and spectral information more efficiently than possible with QSO sightlines. After recalibrating the measurement of galaxy systemic redshifts from their UV spectra, we investigate the kinematics of galaxy-scale outflows via the strong interstellar (IS) absorption and Lya emission lines (when present), as well as their dependence on other physical properties of the galaxies. We construct a sample of 512 close (1-15 arcsec) angular pairs of z~2-3 LBGs in which the spectra background galaxies probe the circumgalactic gas surrrounding those in the foreground. The close pairs, together with spectra of the foreground galaxies themselves, sample galactocentric impact parameters b=0-125 kpc (physical) at =2.2. The ensemble provides a spatial map of cool gas as a function of galactocentric distance for a well-characterized population of galaxies. We propose a simple model that simultaneously matches the kinematics, depth, and profile shape of IS absorption and Lya emission lines, as well as the observed variation of absorption line strength (of HI, CII, CIV, SiII, SiIV) versus galactocentric impact parameter. We discuss the results of the observations in the context of "cold accretion", in which cool gas accretes via filamentary streams directly onto the central regions of galaxies. At present, we find little observational support for cool infalling material, whereas evidence supporting the large-scale effects of outflows is strong. Reconciling theory and observation on the subject of gas flows into and out of forming galaxies seems necessary.Comment: To appear in ApJ; minor revisions to match journal version; added 1 figure, several references, and a subsection discussing the inferred rate of gas outflow into the IG

The Gaseous Environment of High-z Galaxies: Precision Measurements of Neutral Hydrogen in the Circumgalactic Medium of z ~ 2-3 Galaxies in the Keck Baryonic Structure Survey

We present results from the Keck Baryonic Structure Survey (KBSS), a unique spectroscopic survey designed to explore the connection between galaxies and intergalactic baryons. The KBSS is optimized for the redshift range z ~ 2-3, combining S/N ~ 100 Keck/HIRES spectra of 15 hyperluminous QSOs with densely sampled galaxy redshift surveys surrounding each QSO sightline. We perform Voigt profile decomposition of all 6000 HI absorbers within the full Lya forest in the QSO spectra. Here we present the distribution, column density, kinematics, and absorber line widths of HI surrounding 886 star-forming galaxies with 2.0 < z < 2.8 and within 3 Mpc of a QSO sightline. We find that N_HI and the multiplicity of HI components increase rapidly near galaxies. The strongest HI absorbers within ~ 100 physical kpc of galaxies have N_HI ~ 3 dex higher than those near random locations in the IGM. The circumgalactic zone of most enhanced HI absorption (CGM) is found within 300 kpc and 300 km/s of galaxies. Nearly half of absorbers with log(N_HI) > 15.5 are found within the CGM of galaxies meeting our photometric selection, while their CGM occupy only 1.5% of the cosmic volume. The spatial covering fraction, multiplicity of absorption components, and characteristic N_HI remain elevated to transverse distances of 2 physical Mpc. Absorbers with log(N_HI) > 14.5 are tightly correlated with the positions of galaxies, while absorbers with lower N_HI are correlated only on Mpc scales. Redshift anisotropies on Mpc scales indicate coherent infall toward galaxies, while on scales of ~100 physical kpc peculiar velocities of 260 km/s are indicated. The median Doppler widths of absorbers within 1-3 virial radii of galaxies are ~50% larger than randomly chosen absorbers of the same N_HI, suggesting higher gas temperatures and/or increased turbulence likely caused by accretion shocks and/or galactic winds.Comment: Accepted to Ap