Conformational changes in α7 acetylcholine receptors underlying allosteric modulation by divalent cations

Allosteric modulation of membrane receptors is a widespread mechanism by which endogenous and exogenous agents regulate receptor function. For example, several members of the nicotinic receptor family are modulated by physiological concentrations of extracellular calcium ions. In this paper, we examined conformational changes underlying this modulation and compare these with changes evoked by ACh. Two sets of residues in the α7 acetylcholine receptor extracellular domain were mutated to cysteine and analyzed by measuring the rates of modification by the thiol-specific reagent 2-aminoethylmethane thiosulfonate. Using Ba2+ as a surrogate for Ca2+, we found a divalent-dependent decrease the modification rates of cysteine substitutions at M37 and M40, residues at which rates were also slowed by ACh. In contrast, Ba2+ had no significant effect at N52C, a residue where ACh increased the rate of modification. Thus divalent modulators cause some but not all of the conformational effects elicited by agonist. Cysteine substitution of either of two glutamates (E44 or E172), thought to participate in the divalent cation binding site, caused a loss of allosteric modulation, yet Ba2+ still had a significant effect on modification rates of these residues. In addition, the effect of Ba2+ at these residues did not appear to be due to direct occlusion. Our data demonstrate that modulation by divalent cations involves substantial conformational changes in the receptor extracellular domain. Our evidence also suggests the modulation occurs via a binding site distinct from one which includes either (or both) of the conserved glutamates at E44 or E172

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Multi-tissue integrative analysis of personal epigenomes

Evaluating the impact of genetic variants on transcriptional regulation is a central goal in biological science that has been constrained by reliance on a single reference genome. To address this, we constructed phased, diploid genomes for four cadaveric donors (using long-read sequencing) and systematically charted noncoding regulatory elements and transcriptional activity across more than 25 tissues from these donors. Integrative analysis revealed over a million variants with allele-specific activity, coordinated, locus-scale allelic imbalances, and structural variants impacting proximal chromatin structure. We relate the personal genome analysis to the ENCODE encyclopedia, annotating allele- and tissue-specific elements that are strongly enriched for variants impacting expression and disease phenotypes. These experimental and statistical approaches, and the corresponding EN-TEx resource, provide a framework for personalized functional genomics

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Mapping early social development in rodents through the lens of interpersonal synchrony

In humans, parent-child neural synchrony has been shown to support early communication, social attunement and learning. However, very little is known about the developmental origins and sequelae of neural synchrony, and whether this neural mechanism might play a causal role in the control of social and communicative behaviour across species. Rodent models are optimal for exploring such questions of causality, with a plethora of tools available for both disruption/induction (optogenetics) and even mechanistic dissection of synchrony-induction pathways (in vivo electrical or optical recording of neural activity). However, before rodent models can be leveraged to dissect parent-infant synchrony mechanisms, we first need to understand the forms of parent-pup synchrony that occur during rodent development, and their trajectory of change over time. Using longitudinal video and ultrasonic-audio recordings, we followed the naturalistic development of C57/BL6 mice families (n=5) from infancy to adolescence (postnatal day 5 to 35) in a standard home-cage environment. Focusing on behaviours with particular analogies to the human context, we quantified the duration and occurrence of various dam-pup social behaviours that could potentially drive or facilitate synchrony between dam-pup dyads. Quantified behaviours fell into 3 main categories: instrumental, social interactive and vocal communicative behaviours. Reminiscent of human social development, over time we observed a gradual reduction in the frequency of instrumental behaviours (nursing, nest building) and a concomitant increase in social interactive behaviours (allogrooming, social sniffing, social rearing and social play). Several time-specific peaks in social behaviour (maternal licking/grooming, solicitations) were also observed, potentially reflecting the occurrence of crucial social developmental periods. Further, we identified several categories of ultrasonic vocalisations (USVs) that mirrored social behavioural trends (eg. downward calls with nursing or complex calls with solicitations). Akin to human communication, these calls may represent unique social cues involved in establishing and maintaining interpersonal synchrony during successful social interactions. Our results help to elucidate the full spectrum of dam-pup social behaviours that may potentiate synchrony during rodent early development, addressing an important gap in cross-species research on neural synchrony.Ministry of Education (MOE