Experiences with starfield visualizations for analysis of library collections

This paper presents a qualitative and formative study of the uses of a starfield-based visualization interface for analysis of library collections. The evaluation process has produced feedback that suggests ways to significantly improve starfield interfaces and the interaction process to improve their learnability and usability. The study also gave us clear indication of additional potential uses of starfield visualizations that can be exploited by further functionality and interface development. We report on resulting implications for the design and use of starfield visualizations that will impact their graphical interface features, their use for managing data quality and their potential for various forms of visual data mining. Although the current implementation and analysis focuses on the collection of a physical library, the most important contributions of our work will be in digital libraries, in which volume, complexity and dynamism of collections are increasing dramatically and tools are needed for visualization and analysis

H3K56me3 is a novel, conserved heterochromatic mark that largely but not completely overlaps with H3K9me3 in both regulation and localization.

Histone lysine (K) methylation has been shown to play a fundamental role in modulating chromatin architecture and regulation of gene expression. Here we report on the identification of histone H3K56, located at the pivotal, nucleosome DNA entry/exit point, as a novel methylation site that is evolutionary conserved. We identify trimethylation of H3K56 (H3K56me3) as a modification that is present during all cell cycle phases, with the exception of S-phase, where it is underrepresented on chromatin. H3K56me3 is a novel heterochromatin mark, since it is enriched at pericentromeres but not telomeres and is thereby similar, but not identical, to the localization of H3K9me3 and H4K20me3. Possibly due to H3 sequence similarities, Suv39h enzymes, responsible for trimethylation of H3K9, also affect methylation of H3K56. Similarly, we demonstrate that trimethylation of H3K56 is removed by members of the JMJD2 family of demethylases that also target H3K9me3. Furthermore, we identify and characterize mouse mJmjd2E and its human homolog hKDM4L as novel, functionally active enzymes that catalyze the removal of two methyl groups from trimethylated H3K9 and K56. H3K56me3 is also found in C. elegans, where it co-localizes with H3K9me3 in most, but not all, tissues. Taken together, our findings raise interesting questions regarding how methylation of H3K9 and H3K56 is regulated in different organisms and their functional roles in heterochromatin formation and/or maintenance

UvrC Coordinates an O₂-Sensitive [4Fe4S] Cofactor

Recent advances have led to numerous landmark discoveries of [4Fe4S] clusters coordinated by essential enzymes in repair, replication, and transcription across all domains of life. The cofactor has notably been challenging to observe for many nucleic acid processing enzymes due to several factors, including a weak bioinformatic signature of the coordinating cysteines and lability of the metal cofactor. To overcome these challenges, we have used sequence alignments, an anaerobic purification method, iron quantification, and UV–visible and electron paramagnetic resonance spectroscopies to investigate UvrC, the dual-incision endonuclease in the bacterial nucleotide excision repair (NER) pathway. The characteristics of UvrC are consistent with [4Fe4S] coordination with 60–70% cofactor incorporation, and additionally, we show that, bound to UvrC, the [4Fe4S] cofactor is susceptible to oxidative degradation with aggregation of apo species. Importantly, in its holo form with the cofactor bound, UvrC forms high affinity complexes with duplexed DNA substrates; the apparent dissociation constants to well-matched and damaged duplex substrates are 100 ± 20 nM and 80 ± 30 nM, respectively. This high affinity DNA binding contrasts reports made for isolated protein lacking the cofactor. Moreover, using DNA electrochemistry, we find that the cluster coordinated by UvrC is redox-active and participates in DNA-mediated charge transport chemistry with a DNA-bound midpoint potential of 90 mV vs NHE. This work highlights that the [4Fe4S] center is critical to UvrC

UvrC Coordinates an O₂-Sensitive [4Fe4S] Cofactor

Recent advances have led to numerous landmark discoveries of [4Fe4S] clusters coordinated by essential enzymes in repair, replication, and transcription across all domains of life. The cofactor has notably been challenging to observe for many nucleic acid processing enzymes due to several factors, including a weak bioinformatic signature of the coordinating cysteines and lability of the metal cofactor. To overcome these challenges, we have used sequence alignments, an anaerobic purification method, iron quantification, and UV–visible and electron paramagnetic resonance spectroscopies to investigate UvrC, the dual-incision endonuclease in the bacterial nucleotide excision repair (NER) pathway. The characteristics of UvrC are consistent with [4Fe4S] coordination with 60–70% cofactor incorporation, and additionally, we show that, bound to UvrC, the [4Fe4S] cofactor is susceptible to oxidative degradation with aggregation of apo species. Importantly, in its holo form with the cofactor bound, UvrC forms high affinity complexes with duplexed DNA substrates; the apparent dissociation constants to well-matched and damaged duplex substrates are 100 ± 20 nM and 80 ± 30 nM, respectively. This high affinity DNA binding contrasts reports made for isolated protein lacking the cofactor. Moreover, using DNA electrochemistry, we find that the cluster coordinated by UvrC is redox-active and participates in DNA-mediated charge transport chemistry with a DNA-bound midpoint potential of 90 mV vs NHE. This work highlights that the [4Fe4S] center is critical to UvrC

Local Stabilization of Time-Delay Nonlinear Discrete-Time Systems Using Takagi-Sugeno Models and Convex Optimization

A convex condition in terms of linear matrix inequalities (LMIs) is developed for the synthesis of stabilizing fuzzy state feedback controllers for nonlinear discrete-time systems with time-varying delays. A Takagi-Sugeno (T-S) fuzzy model is used to represent exactly the nonlinear system in a restricted domain of the state space, called region of validity. The proposed stabilization condition is based on a Lyapunov-Krasovskii (L-K) function and it takes into account the region of validity to determine a set of initial conditions for which the actual closed-loop system trajectories are asymptotically stable and do not evolve outside the region of validity. This set of allowable initial conditions is determined from the level set associated to a fuzzy L-K function as a Cartesian product of two subsets: one characterizing the set of states at the initial instant and another for the delayed state sequence necessary to characterize the initial conditions. Finally, we propose a convex programming problem to design a fuzzy controller that maximizes the set of initial conditions taking into account the shape of the region of validity of the T-S fuzzy model. Numerical simulations are given to illustrate this proposal

A Foreground Masking Strategy for [CII] Intensity Mapping Experiments Using Galaxies Selected by Stellar Mass and Redshift

Intensity mapping provides a unique means to probe the epoch of reionization (EoR), when the neutral intergalactic medium was ionized by the energetic photons emitted from the first galaxies. The [CII] 158$\mu$m fine-structure line is typically one of the brightest emission lines of star-forming galaxies and thus a promising tracer of the global EoR star-formation activity. However, [CII] intensity maps at $6 \lesssim z \lesssim 8$ are contaminated by interloping CO rotational line emission ($3 \leq J_{\rm upp} \leq 6$) from lower-redshift galaxies. Here we present a strategy to remove the foreground contamination in upcoming [CII] intensity mapping experiments, guided by a model of CO emission from foreground galaxies. The model is based on empirical measurements of the mean and scatter of the total infrared luminosities of galaxies at $z 10^{8}\,\rm M_{\rm \odot}$ selected in $K$-band from the COSMOS/UltraVISTA survey, which can be converted to CO line strengths. For a mock field of the Tomographic Ionized-carbon Mapping Experiment (TIME), we find that masking out the "voxels" (spectral-spatial elements) containing foreground galaxies identified using an optimized CO flux threshold results in a $z$-dependent criterion $m^{\rm AB}_{\rm K} \lesssim 22$ (or $M_{*} \gtrsim 10^{9} \,\rm M_{\rm \odot}$) at $z < 1$ and makes a [CII]/CO$_{\rm tot}$ power ratio of $\gtrsim 10$ at $k=0.1$ $h$/Mpc achievable, at the cost of a moderate $\lesssim 8\%$ loss of total survey volume.Comment: 14 figures, 4 tables, re-submitted to ApJ after addressing reviewer's comments. Comments welcom

IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects