Telomerase and Telomere-Associated Proteins: Structural Insights into Mechanism and Evolution

SummaryRecent advances in our structural understanding of telomerase and telomere-associated proteins have contributed significantly to elucidating the molecular mechanisms of telomere maintenance. The structures of telomerase TERT domains have provided valuable insights into how experimentally identified conserved motifs contribute to the telomerase reverse transcriptase reaction. Additionally, structures of telomere-associated proteins in a variety of organisms have revealed that, across evolution, telomere-maintenance mechanisms employ common structural elements. For example, the single-stranded 3′ overhang of telomeric DNA is specifically and tightly bound by an OB-fold in nearly all species, including ciliates (TEBP and Pot1a), fission yeast (SpPot1), budding yeast (Cdc13), and humans (hPOT1). Structures of the yeast Cdc13, Stn1, and Ten1 proteins demonstrated that telomere maintenance is regulated by a complex that bears significant similarity to the RPA heterotrimer. Similarly, proteins that specifically bind double-stranded telomeric DNA in divergent species use homeodomains to execute their functions (human TRF1 and TRF2 and budding yeast ScRap1). Likewise, the conserved protein Rap1, which is found in budding yeast, fission yeast, and humans, contains a structural motif that is known to be critical for protein-protein interaction. In addition to revealing the common underlying themes of telomere maintenance, structures have also elucidated the specific mechanisms by which many of these proteins function, including identifying a telomere-specific domain in Stn1 and how the human TRF proteins avoid heterodimerization. In this review, we summarize the high-resolution structures of telomerase and telomere-associated proteins and discuss the emergent common structural themes among these proteins. We also address how these high-resolution structures complement biochemical and cellular studies to enhance our understanding of telomere maintenance and function

On the Substitution of Identicals in Counterfactual Reasoning

It is widely held that counterfactuals, unlike attitude ascriptions, preserve the referential transparency of their constituents, i.e., that counterfactuals validate the substitution of identicals when their constituents do. The only putative counterexamples in the literature come from counterpossibles, i.e., counterfactuals with impossible antecedents. Advocates of counterpossibilism, i.e., the view that counterpossibles are not all vacuous, argue that counterpossibles can generate referential opacity. But in order to explain why most substitution inferences into counterfactuals seem valid, counterpossibilists also often maintain that counterfactuals with possible antecedents are transparency‐preserving. I argue that if counterpossibles can generate opacity, then so can ordinary counterfactuals with possible antecedents. Utilizing an analogy between counterfactuals and attitude ascriptions, I provide a counterpossibilist‐friendly explanation for the apparent validity of substitution inferences into counterfactuals. I conclude by suggesting that the debate over counterpossibles is closely tied to questions concerning the extent to which counterfactuals are more like attitude ascriptions and epistemic operators than previously recognized

The Radial Structure of SNR N103B

We report on the results from a Chandra ACIS observation of the young, compact, supernova remnant N103B. The unprecedented spatial resolution of Chandra reveals sub-arcsecond structure, both in the brightness and in spectral variations. Underlying these small-scale variations is a surprisingly simple radial structure in the equivalent widths of the strong Si and S emission lines. We investigate these radial variations through spatially resolved spectroscopy using a plane-parallel, non-equilibrium ionization model with multiple components. The majority of the emission arises from components with a temperature of 1 keV: a fully ionized hydrogen component; a high ionization timescale (n_e*t > 10^12 s cm^-3) component containing Si, S, Ar, Ca, and Fe; and a low ionization timescale (n_e*t ~ 10^{11} s cm^-3) O, Ne, and Mg component. To reproduce the strong Fe Kalpha line, it is necessary to include additional Fe in a hot (> 2 keV), low ionization (n_e*t ~ 10^10.8 s cm^-3) component. This hot Fe may be in the form of hot Fe bubbles, formed in the radioactive decay of clumps of 56Ni. We find no radial variation in the ionization timescales or temperatures of the various components. Rather, the Si and S equivalent widths increase at large radii because these lines, as well as those of Ar and Ca, are formed in a shell occupying the outer half of the remnant. A shell of hot Fe is located interior to this, but there is a large region of overlap between these two shells. In the inner 30% of the remnant, there is a core of cooler, 1 keV Fe. We find that the distribution of the ejecta and the yields of the intermediate mass species are consistent with model prediction for Type Ia events.Comment: 34 pages, including 7 tables and 7 figures, Accepted by Ap

A comparative study of WASP-67b and HAT-P-38b from WFC3 data

Atmospheric temperature and planetary gravity are thought to be the main parameters affecting cloud formation in giant exoplanet atmospheres. Recent attempts to understand cloud formation have explored wide regions of the equilibrium temperature-gravity parameter space. In this study, we instead compare the case of two giant planets with nearly identical equilibrium temperature ($T_\mathrm{eq}$ $\sim 1050 \, \mathrm{K}$) and gravity ($g \sim 10 \, \mathrm{m \, s}^{-1})$. During $HST$ Cycle 23, we collected WFC3/G141 observations of the two planets, WASP-67 b and HAT-P-38 b. HAT-P-38 b, with mass 0.42 M$_\mathrm{J}$ and radius 1.4 $R_\mathrm{J}$, exhibits a relatively clear atmosphere with a clear detection of water. We refine the orbital period of this planet with new observations, obtaining $P = 4.6403294 \pm 0.0000055 \, \mathrm{d}$. WASP-67 b, with mass 0.27 M$_\mathrm{J}$ and radius 0.83 $R_\mathrm{J}$, shows a more muted water absorption feature than that of HAT-P-38 b, indicating either a higher cloud deck in the atmosphere or a more metal-rich composition. The difference in the spectra supports the hypothesis that giant exoplanet atmospheres carry traces of their formation history. Future observations in the visible and mid-infrared are needed to probe the aerosol properties and constrain the evolutionary scenario of these planets.Comment: 16 pages, 17 figures, 8 tables, accepted for publication in The Astronomical Journa

Users’ information disclosure determinants in social networking sites: a systematic literature review

The privacy paradox describes a phenomenon whereby there is no connection between stated privacy concerns and privacy behaviours. We need to understand the underlying reasons for this paradox if we are to help users to preserve their privacy more effectively. In particular, the Social Networking System (SNS) domain offers a rich area of investigation due to the risks of unwise information disclosure decisions. Our study thus aims to untangle the complicated nature and underlying mechanisms of online privacy-related decisions in SNSs. In this paper, we report on the findings of a Systematic Literature Review (SLR) that revealed a number of factors that are likely to influence online privacy decisions. Our deductive analysis approach was informed by Communicative Privacy Management (CPM) theory. We uncovered a lack of clarity around privacy attitudes and their link to behaviours, which makes it challenging to design privacy-protecting SNS platforms and to craft legislation to ensure that users’ privacy is preserved

Discovery of Fur binding site clusters in Escherichia coli by information theory models

Fur is a DNA binding protein that represses bacterial iron uptake systems. Eleven footprinted Escherichia coli Fur binding sites were used to create an initial information theory model of Fur binding, which was then refined by adding 13 experimentally confirmed sites. When the refined model was scanned across all available footprinted sequences, sequence walkers, which are visual depictions of predicted binding sites, frequently appeared in clusters that fit the footprints (∼83% coverage). This indicated that the model can accurately predict Fur binding. Within the clusters, individual walkers were separated from their neighbors by exactly 3 or 6 bases, consistent with models in which Fur dimers bind on different faces of the DNA helix. When the E. coli genome was scanned, we found 363 unique clusters, which includes all known Fur-repressed genes that are involved in iron metabolism. In contrast, only a few of the known Fur-activated genes have predicted Fur binding sites at their promoters. These observations suggest that Fur is either a direct repressor or an indirect activator. The Pseudomonas aeruginosa and Bacillus subtilis Fur models are highly similar to the E. coli Fur model, suggesting that the Fur–DNA recognition mechanism may be conserved for even distantly related bacteria