Metal retention and replacement in QueD2 protect queuosine-tRNA biosynthesis in metal-starved Acinetobacter baumannii.

In response to bacterial infection, the vertebrate host employs the metal-sequestering protein calprotectin (CP) to withhold essential transition metals, notably Zn(II), to inhibit bacterial growth. Previous studies of the impact of CP-imposed transition-metal starvation in A. baumannii identified two enzymes in the de novo biosynthesis pathway of queuosine-transfer ribonucleic acid (Q-tRNA) that become cellularly abundant, one of which is QueD2, a 6-carboxy-5,6,7,8-tetrahydropterin (6-CPH4) synthase that catalyzes the initial, committed step of the pathway. Here, we show that CP strongly disrupts Q incorporation into tRNA. As such, we compare the AbQueD2 "low-zinc" paralog with a housekeeping, obligatory Zn(II)-dependent enzyme QueD. The crystallographic structure of Zn(II)-bound AbQueD2 reveals a distinct catalytic site coordination sphere and assembly state relative to QueD and possesses a dynamic loop, immediately adjacent to the catalytic site that coordinates a second Zn(II) in the structure. One of these loop-coordinating residues is an invariant Cys18, that protects QueD2 from dissociation of the catalytic Zn(II) while maintaining flux through the Q-tRNA biosynthesis pathway in cells. We propose a "metal retention" model where Cys18 introduces coordinative plasticity into the catalytic site which slows metal release, while also enhancing the metal promiscuity such that Fe(II) becomes an active cofactor. These studies reveal a complex, multipronged evolutionary adaptation to cellular Zn(II) limitation in a key Zn(II) metalloenzyme in an important human pathogen.

Weakness After an Intra-articular Steroid Injection: A Case Report of Acute Steroid-induced Myopathy.

INTRODUCTION: Weakness is a common chief complaint in the emergency department, and the use of glucocorticoids is pervasive in medicine. Muscle weakness, or myopathy, is a well documented side effect of chronic glucocorticoid use. However, acute myopathy, with an onset shortly after initiation of glucocorticoids, is much rarer. CASE REPORT: We present a case of acute steroid-induced myopathy after a single intra-articular dose of triamcinolone in a young, healthy, active male. To our knowledge, this is the first case described in the medical literature of acute steroid-induced myopathy following a single intra-articular injection. CONCLUSION: In a patient who presents with proximal muscle weakness and has a history of glucocorticoid use, the diagnosis of steroid-induced myopathy should be considered. Acute steroid-induced myopathy should be high on the differential in a patient who presents with typical symptoms and has been prescribed glucocorticoids for less than 14 days or, in rare cases, may have recently received a single dose of glucocorticoids. Treatment is supportive and outpatient management is typically indicated, as respiratory muscle involvement is rare.

Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis.

Zinc (Zn) is an essential micronutrient and cofactor for up to 10% of proteins in living organisms. During Zn limitation, specialized enzymes called metallochaperones are predicted to allocate Zn to specific metalloproteins. This function has been putatively assigned to G3E GTPase COG0523 proteins, yet no Zn metallochaperone has been experimentally identified in any organism. Here, we functionally characterize a family of COG0523 proteins that is conserved across vertebrates. We identify Zn metalloprotease methionine aminopeptidase 1 (METAP1) as a COG0523 client, leading to the redesignation of this group of COG0523 proteins as the Zn-regulated GTPase metalloprotein activator (ZNG1) family. Using biochemical, structural, genetic, and pharmacological approaches across evolutionarily divergent models, including zebrafish and mice, we demonstrate a critical role for ZNG1 proteins in regulating cellular Zn homeostasis. Collectively, these data reveal the existence of a family of Zn metallochaperones and assign ZNG1 an important role for intracellular Zn trafficking.

Corporate insecthood.

Whether the corporation should be considered a person is a matter of active academic and public debate. Here, we examine whether, and in what ways, ordinary citizens conceptualize the corporation as a person. We present evidence that corporations are anthropomorphized, but only to a certain degree. Compared with other entities, the average corporation is considered about as similar to a person as an ant. Corporations differ in the extent to which people are willing to grant them personhood however, and this pattern is predicted by how salient the organization's mental and moral traits are. This process of anthropomorphization has important downstream consequences, increasing support for granting legal rights and responsibilities to corporations. Because our studies show that this relationship also obtains for animals, we conclude that perceptions of corporate personhood draw on a more general set of rules for assessing an entity's personhood.

COG0523 proteins: a functionally diverse family of transition metal-regulated G3E P-loop GTP hydrolases from bacteria to man.

Transition metal homeostasis ensures that cells and organisms obtain sufficient metal to meet cellular demand while dispensing with any excess so as to avoid toxicity. In bacteria, zinc restriction induces the expression of one or more Zur (zinc-uptake repressor)-regulated Cluster of Orthologous Groups (COG) COG0523 proteins. COG0523 proteins encompass a poorly understood sub-family of G3E P-loop small GTPases, others of which are known to function as metallochaperones in the maturation of cobalamin (CoII) and NiII cofactor-containing metalloenzymes. Here, we use genomic enzymology tools to functionally analyse over 80 000 sequences that are evolutionarily related to Acinetobacter baumannii ZigA (Zur-inducible GTPase), a COG0523 protein and candidate zinc metallochaperone. These sequences segregate into distinct sequence similarity network (SSN) clusters, exemplified by the ZnII-Zur-regulated and FeIII-nitrile hydratase activator CxCC (C, Cys; X, any amino acid)-containing COG0523 proteins (SSN cluster 1), NiII-UreG (clusters 2, 8), CoII-CobW (cluster 4), and NiII-HypB (cluster 5). A total of five large clusters that comprise ≈ 25% of all sequences, including cluster 3 which harbors the only structurally characterized COG0523 protein, Escherichia coli YjiA, and many uncharacterized eukaryotic COG0523 proteins. We also establish that mycobacterial-specific protein Y (Mpy) recruitment factor (Mrf), which promotes ribosome hibernation in actinomycetes under conditions of ZnII starvation, segregates into a fifth SSN cluster (cluster 17). Mrf is a COG0523 paralog that lacks all GTP-binding determinants as well as the ZnII-coordinating Cys found in CxCC-containing COG0523 proteins. On the basis of this analysis, we discuss new perspectives on the COG0523 proteins as cellular reporters of widespread nutrient stress induced by ZnII limitation.

Distinct correlates of empathy and compassion with burnout and affective symptoms in health professionals and students

Objective: The causes of high rates of psychological distress among health professionals and students are largely unknown. Health professionals respond to those who are in distress with empathy (feeling what others feel) or compassion (caring about what others feel). This study aims to investigate whether empathy and compassion are distinct traits and how both traits are associated with negative affect (burnout, depression, anxiety and anger symptoms) in undergraduate students and professionals in medicine, psychology and nursing. Methods: A sample of 464 students and professionals filled out an online protocol with a sociodemographic data questionnaire and self-report questionnaires covering the variables of interest. Results: The findings indicate that empathy is associated with higher negative affect, while compassion is associate with lower negative affect, which suggests that they are different traits. Conclusion: Our findings provide new evidence that the well-being of health professionals might be affected differently depending on socioemotional traits relevant to emotional connection.

Distinct correlates of empathy and compassion with burnout and affective symptoms in health professionals and students.

OBJECTIVE: The causes of high rates of psychological distress among health professionals and students are largely unknown. Health professionals respond to those who are in distress with empathy (feeling what others feel) or compassion (caring about what others feel). This study aims to investigate whether empathy and compassion are distinct traits and how both traits are associated with negative affect (burnout, depression, anxiety and anger symptoms) in undergraduate students and professionals in medicine, psychology and nursing. METHODS: A sample of 464 students and professionals filled out an online protocol with a sociodemographic data questionnaire and self-report questionnaires covering the variables of interest. RESULTS: The findings indicate that empathy is associated with higher negative affect, while compassion is associate with lower negative affect, which suggests that they are different traits. CONCLUSION: Our findings provide new evidence that the well-being of health professionals might be affected differently depending on socioemotional traits relevant to emotional connection.

Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors.

Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents.

Multi-metal nutrient restriction and crosstalk in metallostasis systems in microbial pathogens.

Transition metals from manganese to zinc function as catalytic and structural cofactors for an amazing diversity of proteins and enzymes, and thus are essential for all forms of life. During infection, inflammatory host proteins limit the accessibility of multiple transition metals to invading pathogens in a process termed nutritional immunity. In order to respond to host-mediated metal starvation, bacteria employ both protein and RNA-based mechanisms to sense prevailing transition metal concentrations that collectively regulate systems-level strategies to maintain cellular metallostasis. In this review, we discuss a number of recent advances in our understanding of how bacteria orchestrate the adaptive response to host-mediated multi-metal restriction, highlighting crosstalk among these regulatory systems.

The developmental origins of risk and time preferences across diverse societies.

Risk and time preferences have often been viewed as reflecting inherent traits such as impatience and self-control. Here, we offer an alternative perspective, arguing that they are flexible and environmentally informed. In Study 1, we investigated risk and time preferences among children in the United States, India, and Argentina, as well as forager-horticulturalist Shuar children in Amazonian Ecuador. We find striking cross-cultural differences in behavior: children in India, the United States, and Argentina are more risk-seeking and future-oriented, whereas Shuar children are more risk-averse and exhibit more heterogeneous time preferences, on average preferring more today choices. To explore 1 of the socioecological forces that may be shaping these preferences, in Study 2, we compared the behavior of more and less market-integrated Shuar children, finding that those in market-integrated regions are more future-oriented and risk-seeking. These findings indicate that cross-cultural differences in risk and time preferences can be traced into childhood and may be influenced by the local environment. More broadly, our results contribute to a growing understanding of plasticity and variation in the development of behavior. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Mechanistic Insights into the Metal-Dependent Activation of ZnII-Dependent Metallochaperones.

Members of the COG0523 subfamily of candidate GTPase metallochaperones function in bacterial transition-metal homeostasis, but the nature of the cognate metal, mechanism of metal transfer, and identification of target protein(s) for metal delivery remain open questions. Here, we explore the multifunctionality of members of the subfamily linked to delivering ZnII to apoprotein targets under conditions of host-imposed transition-metal depletion. We examine two zinc-uptake repressor (Zur)-regulated COG0523 family members, each from a major human pathogen, Acinetobacter baumannii (AbZigA) and Staphylococcus aureus (SaZigA), in an effort to develop a model for ZnII metallochaperone activity. ZnII chelator competition experiments reveal one high-affinity (KZn1 ≈ 1010-1011 M-1) metal-binding site in each GTPase, while AbZigA and SaZigA are characterized by an additional one and two (lower-affinity) metal-binding sites, respectively. CoII titrations reveal that both metallochaperones have similar electronic absorption characteristics that indicate the presence of two tetrahedral metal coordination sites. High-affinity metal binding at the CXCC motif activates the GTPase activity of both enzymes, with ZnII more effective than CoII. Both GTPases bind the product, GDP, more tightly in the apoprotein than the ZnII-bound state and exhibit what is best described as a "locked" conformation around the GTP substrate. Negative thermodynamic linkage is observed between nucleotide binding and metal binding, leading to a new mechanistic model for COG0523-catalyzed metal delivery.

Perspective taking failures in the valuation of mind and body.

Accurately inferring the values and preferences of others is crucial for successful social interactions. Nevertheless, without direct access to others' minds, perspective taking errors are common. Across 5 studies, we demonstrate a systematic perspective taking failure: People believe they value their minds more than others do and often believe they value their bodies less than others do. The bias manifests across a variety of domains and measures, from judgments about the severity of injuries to preferences for new abilities to assessments of how much one is defined by their mind and body. This perspective taking failure was diminished-but still present-when participants thought of a close other. Finally, we assess and find evidence for the notion that this perspective taking failure is a function of the fact that others' minds are less salient than others' bodies. It appears to be the case that people believe the most salient cue from a target is also the best indicator of their values and preferences. This bias has implications for the ways in which we create social policy, judge others' actions, make choices on behalf of others, and allocate resources to the physically and mentally ill. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Preemptive Analgesia Decreases Pain Following Anorectal Surgery: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND: Postoperative pain is a frequent cause for delayed discharge following outpatient procedures, including anorectal surgery. Both central and peripheral pain receptor sensitization are thought to contribute to postoperative pain. Blocking these receptors and preempting sensitization prevents hyperalgesia leading to lower pain medication requirements. Studies in the orthopedic, urologic, and gynecologic literature support this practice, but the use of preemptive analgesia in anorectal surgery is understudied. OBJECTIVE: This study aimed to evaluate the effectiveness of preemptive analgesia in decreasing postoperative pain. DESIGN: This is a randomized, double-blinded, placebo-controlled trial. SETTING: This study was conducted at the University of Vermont Medical Center, a tertiary care referral center in Burlington, Vermont. PATIENTS: Patients who were over 18 years of age, ASA Physical Status Classes I, II, or III, and undergoing surgery for anal fissure, fistula or condyloma or hemorrhoids were selected. INTERVENTIONS: Preoperative oral acetaminophen and gabapentin followed by intravenous ketamine and dexamethasone were given before incision compared with oral placebos. MAIN OUTCOME MEASURES: The primary outcomes measured were postoperative pain scores, percentage of patients utilizing breakthrough narcotics, and rates of side effects. RESULTS: Ninety patients were enrolled. Because of patient withdrawal, screen failures, and loss to follow-up, 61 patients were analyzed (30 in the preemptive analgesia group and 31 in the control group). Patients in the active group had significantly less pain in the postanesthesia care unit and at 8 hours postoperatively. Significantly fewer participants in the active group used narcotics in the postanesthesia care unit and at 8 hours postoperatively. Average pain scores were excellent for both groups. There was no difference in the number of medication-related side effects between the 2 groups. LIMITATIONS: This study was limited by the small sample size and excellent pain control in both groups. CONCLUSIONS: Preemptive analgesia is safe and results in decreased pain in the early postoperative period following anorectal surgery. It should be implemented by surgeons performing these procedures. See Video Abstract at http://links.lww.com/DCR/A588.

Implementation of the universal BLS termination of resuscitation rule in a rural EMS system.

BACKGROUND: Emergency Medical Services (EMS) are often the first medical providers to begin resuscitation of out-of-hospital cardiac arrest (OHCA) victims. The universal Basic Life Support Termination of Resuscitation (BLS-TOR) rule is a validated clinical prediction tool used to identify patients in which continued resuscitation efforts are futile. OBJECTIVE: The primary aim is to compare the rate of transport of OHCA cases before and after the implementation of a BLS-TOR protocol and to determine the compliance rate of EMS personnel with the new protocol in a largely volunteer, rural system. METHODS: A retrospective cohort study was conducted using the statewide EMS electronic patient care report system. Cases were identified by searching for any incident that had a primary impression of "cardiac arrest" or a primary symptom of "cardiorespiratory arrest" or "death." Data were collected from the two years prior to and following implementation of the BLS-TOR rule from January 1, 2012 through March 31, 2016. RESULTS: There were 702 OHCA cases were identified, with 329 cases meeting inclusion criteria. The transport rate was 91.1% in the pre-intervention group compared with 69.4% in the post-intervention group (χ2=24.8; p<0.001). EMS compliance rate with the BLS-TOR rule was 66.7%. Of the 265 patients transported during the study, 87 patients met (post-intervention group; n=22) or retrospectively met (pre-intervention group; n=65) the BLS-TOR requirements for field termination of resuscitation. None of these patients survived to hospital discharge. CONCLUSION: Rural EMS systems may benefit from implementation and utilization of the universal BLS-TOR rule.

The behavioral constellation of deprivation may be best understood as risk management.

Although the authors make a compelling case that early-life deprivation leads to present orientation, we believe that such behaviors may be better understood in terms of an underlying risk-management strategy, in which those who experience such deprivation are more risk-averse. The model we sketch accommodates the authors' present-orientation observations and further explains differences in risk preferences and social preferences.

Are empathy and concern psychologically distinct?

Researchers have long been interested in the relationship between feeling what you believe others feel-often described as empathy-and caring about the welfare of others-often described as compassion or concern. Many propose that empathy is a prerequisite for concern and is therefore the ultimate motivator of prosocial actions. To assess this hypothesis, the authors developed the Empathy Index, which consists of 2 novel scales, and explored their relationship to a measure of concern as well as to measures of cooperative and altruistic behavior. A series of factor analyses reveal that empathy and concern consistently load on different factors. Furthermore, they show that empathy and concern motivate different behaviors: concern for others is a uniquely positive predictor of prosocial action whereas empathy is either not predictive or negatively predictive of prosocial actions. Together these studies suggest that empathy and concern are psychologically distinct and empathy plays a more limited role in our moral lives than many believe. (PsycINFO Database Record

Cultural evolution need not imply group selection.

Richerson et al. make a compelling case for cultural evolution. In focusing on cultural group selection, however, they neglect important individual-level accounts of cultural evolution. While scientific discourse typically links cultural evolution to group selection and genetic evolution to individual selection, this association is due to historical accident only. We thus call for more consideration of individual-level cultural evolution.

A Longitudinal Assessment of Associations between Adolescent Environment, Adversity Perception, and Economic Status on Fertility and Age of Menarche.

PURPOSE: Perceptions of environmental adversity and access to economic resources in adolescence can theoretically affect the timing of life history transitions and investment in reproductive effort. Here we present evidence of correlations between variables associated with subjective extrinsic mortality, economic status, and reproductive effort in a nationally representative American population of young adults. METHODS: We used a longitudinal database that sampled American participants (N ≥ 1,579) at four points during early adolescence and early adulthood to test whether perceptions of environmental adversity and early economic status were associated with reproductive effort. RESULTS: We found that subjectively high ratings of environmental danger and low access to economic resources in adolescence were significantly associated with an earlier age of menarche in girls and earlier, more robust fertility in young adulthood. CONCLUSION: While energetics and somatic condition remain as possible sources of variation, the results of this study support the hypothesis that perceptions of adversity early in life and limited access to economic resources are associated with differences in reproductive effort and scheduling. How these factors may covary with energetics and somatic condition merits further investigation.