Fast-transient Searches in Real Time with ZTFReST: Identification of Three Optically-discovered Gamma-ray Burst Afterglows and New Constraints on the Kilonova Rate

While optical surveys regularly discover slow transients like supernovae on their own, the most common way to discover extragalactic fast transients, fading away in a few nights, is via follow-up observations of gamma-ray burst and gravitational-wave triggers. However, wide-field surveys have the potential to also identify rapidly fading transients independently of such external triggers. The volumetric survey speed of the Zwicky Transient Facility (ZTF) makes it sensitive to faint and fast-fading objects as kilonovae, the optical counterparts to binary neutron stars and neutron star-black hole mergers, out to almost 200Mpc. We introduce an open-source software infrastructure, the ZTF REaltime Search and Triggering, ZTFReST, designed to identify kilonovae and fast optical transients in ZTF data. Using the ZTF alert stream combined with forced photometry, we have implemented automated candidate ranking based on their photometric evolution and fitting to kilonova models. Automated triggering of follow-up systems, such as Las Cumbres Observatory, has also been implemented. In 13 months of science validation, we found several extragalactic fast transients independent of any external trigger (though some counterparts were identified later), including at least one supernova with post-shock cooling emission, two known afterglows with an associated gamma-ray burst, two known afterglows without any known gamma-ray counterpart, and three new fast-declining sources (ZTF20abtxwfx, ZTF20acozryr, and ZTF21aagwbjr) that are likely associated with GRB200817A, GRB201103B, and GRB210204A. However, we have not found any objects which appear to be kilonovae; therefore, we constrain the rate of GW170817-like kilonovae to $R < 900$Gpc$^{-3}$yr$^{-1}$. A framework such as ZTFReST could become a prime tool for kilonova and fast transient discovery with the Vera C. Rubin Observatory

Topological Analysis of Small Leucine-Rich Repeat Proteoglycan Nyctalopin

Nyctalopin is a small leucine rich repeat proteoglycan (SLRP) whose function is critical for normal vision. The absence of nyctalopin results in the complete form of congenital stationary night blindness. Normally, glutamate released by photoreceptors binds to the metabotropic glutamate receptor type 6 (GRM6), which through a G-protein cascade closes the non-specific cation channel, TRPM1, on the dendritic tips of depolarizing bipolar cells (DBCs) in the retina. Nyctalopin has been shown to interact with TRPM1 and expression of TRPM1 on the dendritic tips of the DBCs is dependent on nyctalopin expression. In the current study, we used yeast two hybrid and biochemical approaches to investigate whether murine nyctalopin was membrane bound, and if so by what mechanism, and also whether the functional form was as a homodimer. Our results show that murine nyctalopin is anchored to the plasma membrane by a single transmembrane domain, such that the LRR domain is located in the extracellular space

Synthesis of macrocyclic receptors with intrinsic fluorescence featuring quinizarin moieties

An unprecedented class of macrocycles with intrinsic fluorescence consisting of phenolic trimers and quinizarin is developed. Though they are lacking strong hydrogen bonds as observed in calixarenes, the two examples introduced here each adopt a vase-like conformation with all four aromatic units pointing in one direction (syn orientation). This “cone” conformation has been confirmed by NMR spectroscopy, molecular modeling, and X-ray crystallography. The laminar, electron-rich fluorophore as part of the macrocycle allows additional contacts to enclosed guest molecules

The long-active afterglow of GRB 210204A: detection of the most delayed flares in a gamma-ray burst

We present results from extensive broadband follow-up of GRB 210204A over the period of 30 d. We detect optical flares in the afterglow at 7.6 × 105 s and 1.1 × 106 s after the burst: the most delayed flaring ever detected in a GRB afterglow. At the source redshift of 0.876, the rest-frame delay is 5.8 × 105 s (6.71 d). We investigate possible causes for this flaring and conclude that the most likely cause is a refreshed shock in the jet. The prompt emission of the GRB is within the range of typical long bursts: it shows three disjoint emission episodes, which all follow the typical GRB correlations. This suggests that GRB 210204A might not have any special properties that caused late-time flaring, and the lack of such detections for other afterglows might be resulting from the paucity of late-time observations. Systematic late-time follow-up of a larger sample of GRBs can shed more light on such afterglow behaviour. Further analysis of the GRB 210204A shows that the late-time bump in the light curve is highly unlikely due to underlying SNe at redshift (z) = 0.876 and is more likely due to the late-time flaring activity. The cause of this variability is not clearly quantifiable due to the lack of multiband data at late-time constraints by bad weather conditions. The flare of GRB 210204A is the latest flare detected to date

Recent advances in the development of aryl-based foldamers.

In recent years, significant effort has gone into making synthetic oligomers that can attain well-defined conformations analogous to the folding of biomolecules. The diversity of the structural building blocks ranges from peptidic and other aliphatic repeat units to aromatic ones, which do not have a natural counterpart. In this critical review, we will focus on the developments in aromatic foldamers in the last two years and their potential applications. This review will be of interest to people working on the structural and functional mimicry of biomolecules and will, we hope, stimulate further research into novel applications (149 references)

alpha-Helix mimetics as inhibitors of protein-protein interactions.

The inhibition of protein-protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the alpha-helix; these residues frequently play a key role in mediating protein-protein interactions. The first-generation terphenyl scaffold, with a 3,2',2''-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-X(L)-Bak and the p53-hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules

Recent advances in the development of aryl-based foldamers.

In recent years, significant effort has gone into making synthetic oligomers that can attain well-defined conformations analogous to the folding of biomolecules. The diversity of the structural building blocks ranges from peptidic and other aliphatic repeat units to aromatic ones, which do not have a natural counterpart. In this critical review, we will focus on the developments in aromatic foldamers in the last two years and their potential applications. This review will be of interest to people working on the structural and functional mimicry of biomolecules and will, we hope, stimulate further research into novel applications (149 references)

A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes.

Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are on pathway to fiber formation. IAPP is not normally amyloidogenic as its cosecreted partner, insulin, prevents self-assembly. Here, we show that IS5 inhibition is synergistic with insulin. IS5 therefore represents a new approach to amyloid inhibition as the target is an assembly intermediate that may additionally restore functional IAPP expression