The Role of Stellar Feedback in Galaxy Evolution

Aiming at understanding the role of stellar feedback in galaxy evolution, I present a study of the hot interstellar medium in several representative galaxies, based primarily on X-ray observations as well as theoretical modelling. I find that, in the massive disk galaxies NGC2613 and M104, the observed amount of hot gas is much less than that predicted by current galaxy formation models. Such a discrepancy suggests a lack of appropriate treatments of stellar/AGN feedback in these models. I also find that stellar feedback, primarily in the form of mass loss from evolved stars and energy released from supernovae, and presumably consumed by the hot gas, is largely absent from the inner regions of M104, a galaxy of a substantial content of evolved stars but little current star formation. A natural understanding of this phenomenon is that the hot gas is in the form of a galactic-scale outflow, by which the bulk of the stellar feedback is transported to the outer regions and perhaps into the intergalactic space. A comparison between the observed sub-galactic gas structures and model predictions indicate that this outflow is probably subsonic rather than being a classical supersonic galactic wind. Such outflows are likely prevalent in most early-type galaxies of intermediate masses in the present-day universe and thus play a crucial role in the evolution of such galaxies. For the first time I identify the presence of diffuse hot gas in and around the bulge of the Andromeda Galaxy (M31), our well-known neighbor. Both the morphology and energetics of the hot gas suggest that it is also in the form of a large-scale outflow. Assisted with multiwavelength observations toward the circumnuclear regions of M31, I further reveal the relation between the hot gas and other cooler phases of the interstellar medium. I suggest that thermal evaporation, mostly likely energized by Type Ia supernovae, acts to continuously turn cold gas into hot, a process that naturally leads to the inactivity of the central supermassive blackhole as well as the launch of the hot gas outflow. Such a mechanism plays an important role in regulating the multi-phase interstellar medium in the circumnuclear environment and transporting stellar feedback to the outer galactic regions

Molecular engineering of conotoxins: The importance of loop size to alpha-conotoxin structure and function

alpha-Conotoxins are competitive antagonists of nicotinic acetylcholine receptors (nAChRs). The majority of currently characterized alpha-conotoxins have a 4/7 loop size, and the major features of neuronal alpha-conotoxins include a globular disulfide connectivity and a helical structure centered around the third of their four cysteine residues. In this study, a novel "molecular pruning" approach was undertaken to define the relationship between loop size, structure, and function of a-conotoxins. This involved the systematic truncation of the second loop in the a-conotoxin [A10L]PnIA [4/7], a potent antagonist of the alpha 7 nAChR. The penalty for truncation was found to be decreased conformational stability and increased susceptibility to disulfide bond scrambling. Truncation down to 4/4[A10L]PnIA maintained helicity and did not significantly reduce electrophysiological activity at alpha 7 nAChRs, whereas 4/3[AIOL]PnIA lost both alpha 7 nAChR activity and helicity. In contrast, all truncated analogues lost similar to 100-fold affinity at the AMP, a model protein for the extracellular domain of the nAChR. Docking simulations identified several hydrogen bonds lost upon truncation that provide an explanation for the reduced affinities observed at the alpha 7 nAChR and AChBP

Structural determinants of selective α-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP

The nicotinic acetylcholine receptor (nAChR) is the prototype member of the superfamily of pentameric ligand-gated ion channels. How the extracellular ligand-binding domain coordinates selective binding of ligand molecules to different subtypes of the receptor is unknown at the structural level. Here, we present the 2.2-Å crystal structure of a homolog of the ligand-binding domain of the nAChR, Aplysia californica AChBP (Ac-AChBP), in complex with α-conotoxin ImI. This conotoxin is unique in its selectivity toward the neuronal α(3)β(2) and α(7) nAChR, a feature that is reflected in its selective binding to Ac-AChBP compared with other AChBP homologs. We observe a network of interactions between the residues of the ligand-binding site and the toxin, in which ImI Arg-7 and Trp-10 play a key role. The toxin also forms interactions in the ligand-binding site that were not seen in the complex of Ac-AChBP with PnIA(A10L D14K), a conotoxin variant that lacks binding selectivity to AChBP homologs. In combination with electrophysiological recordings obtained by using the wild-type α(7) nAChR and L247T mutant, we show that conotoxin ImI inhibits ion conduction by stabilizing the receptor in a desensitized conformation. Comparison of the Ac-AChBP–ImI crystal structure with existing AChBP structures offers structural insight into the extent of flexibility of the interface loops and how their movement may couple ligand binding to channel gating in the context of a nAChR

The impact of the COVID-19 lockdown on retinopathy of prematurity screening and management in the United States: a multicenter study

To study the effect of the pandemic-related lockdown (physical distance measures and movement restrictions) on the characteristics and management of retinopathy of prematurity (ROP). In this controlled, multicenter cohort study, the medical records of patients born prematurely and screened for ROP in the neonatal intensive care unit during four time periods were reviewed retrospectively: (1) November 1, 2018, to March 15, 2019; (2) March 16, 2019, to August 2, 2019 (lockdown control period); (3) November 1, 2019, to March 15, 2020; and (4) March 16, 2020-August 2, 2020. A total of 1,645 patients met inclusion criteria. Among the 1,633 patients with complete data, mean gestational age (GA) at birth was 28.2, 28.4, 28.0, and 28.3 weeks across time periods 1 to 4, respectively (P = 0.16). The mean birth weight of all patients was 1079.1 ± 378.60 g, with no significant variation across time periods (P = 0.08). There were fewer patients screened during the lockdown period (n = 411) compared with the period immediately before (n = 491) and the same period in the prior year (n = 533). Significantly more patients were screened using indirect ophthalmoscopy, compared to digital imaging (telemedicine), during the lockdown (P < 0.01). There were 11.7%, 7.7%, 9.0%, and 8.8% of patients requiring treatment in each time period, respectively (P = 0.42), with a median postmenstrual age at initial treatment of 37.2, 36.45, 37.1, and 36.3 weeks, respectively (P = 0.32). We recorded a decrease in the number of infants meeting criteria for ROP screening during the lockdown. The GA at birth and birth weight did not differ. Significantly more infants were screened with indirect ophthalmoscopy, compared to digital imaging, during the lockdown

Potencies and selectivities of inhibitors of acetylcholinesterase and its molecular forms in normal and Alzheimer's disease brain

Eight inhibitors of acetylcholinesterase (AChE), tacrine, bis-tacrine, donepezil, rivastigmine, galantamine, heptyl-physostigmine, TAK-147 and metrifonate, were compared with regard to their effects on AChE and butyrylcholinesterase (BuChE) in normal human brain cortex. Additionally, the IC50 values of different molecular forms of AChE (monomeric, G1, and tetrameric, G4) were determined in the cerebral cortex in both normal and Alzheimer’s human brains. The most selective AChE inhibitors, in decreasing sequence, were in order: TAK-147, donepezil and galantamine. For BuChE, the most specific was rivastigmine. However, none of these inhibitors was absolutely specific for AChE or BuChE. Among these inhibitors, tacrine, bis-tacrine, TAK-147, metrifonate and galantamine inhibited both the G1 and G4 AChE forms equally well. Interestingly, the AChE molecular forms in Alzheimer samples were more sensitive to some of the inhibitors as compared with the normal samples. Only one inhibitor, rivastigmine, displayed preferential inhibition for the G1 form of AChE. We conclude that a molecular form-specific inhibitor may have therapeutic applications in inhibiting the G1 form, which is relatively unchanged in Alzheimer’s brain