cells evade inducible parE toxin expression by reducing plasmid copy number.

Unlabelled: Plasmids play important roles in microbial ecosystems, serving as carriers of antibiotic resistance and virulence. In the laboratory, they are essential tools for genetic manipulation and recombinant protein expression. We uncovered an intriguing survival phenotype in a fraction of the bacterial population while using plasmid-mediated arabinose-inducible gene expression to monitor the production of toxic ParE proteins.

Adaptation to seasonal reproduction and environment-associated factors drive temporal and spatial differentiation in northwest Atlantic herring despite gene flow.

Understanding how marine organisms adapt to local environments is crucial for predicting how populations will respond to global climate change. The genomic basis, environmental factors and evolutionary processes involved in local adaptation are however not well understood. Here we use Atlantic herring, an abundant, migratory and widely distributed marine fish with substantial genomic resources, as a model organism to evaluate local adaptation.

Friend or Foe: Protein Inhibitors of DNA Gyrase.

DNA gyrase is essential for the successful replication of circular chromosomes, such as those found in most bacterial species, by relieving topological stressors associated with unwinding the double-stranded genetic material. This critical central role makes gyrase a valued target for antibacterial approaches, as exemplified by the highly successful fluoroquinolone class of antibiotics. It is reasonable that the activity of gyrase could be intrinsically regulated within cells, thereby helping to coordinate DNA replication with doubling times.

Structure-Activity Relationships of Ligand Binding to Oxysterol-Binding Protein (OSBP) and OSBP-Related Protein 4.

Oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4) have emerged as potentially druggable targets in antiviral and precision cancer drug development. Multiple structurally diverse small molecules function through targeting the OSBP/ORP family of proteins, including the antiviral steroidal compounds OSW-1 and T-00127-HEV2. Here, the structure-activity relationships of oxysterols and related compound binding to human OSBP and ORP4 are characterized.

Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure-Activity Relationships and Mechanism of Action.

Antibiotic resistance among bacteria puts immense strain on public health. The discovery of new antibiotics that work through unique mechanisms is one important pillar toward combating this threat of resistance. A functionalized amino dihydropyrimidine was reported to exhibit antibacterial activity via the inhibition of dihydrofolate reductase, an underexploited antibacterial target.

ParD Antitoxin Hotspot Alters a Disorder-to-Order Transition upon Binding to Its Cognate ParE Toxin, Lessening Its Interaction Affinity and Increasing Its Protease Degradation Kinetics.

Type-II toxin-antitoxin (TA) systems are comprised of two tightly interacting proteins, and operons encoding these systems have been identified throughout the genomes of bacteria. In contrast to secretion system effector-immunity pairs, TA systems must remain paired to protect the host cell from toxicity. Continual depletion of the antitoxin results in a shorter half-life than that of the toxin, though it is unclear if antitoxins can be effectively degraded when complexed with toxins.

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Isopentenyl phosphate kinases (IPKs) catalyze the ATP-dependent phosphorylation of isopentenyl monophosphate (IP) to isopentenyl diphosphate (IPP) in the alternate mevalonate pathways of the archaea and plant cytoplasm. In recent years, IPKs have also been employed in artificial biosynthetic pathways called "(iso) prenol pathways" that utilize promiscuous kinases to sequentially phosphorylate (iso) prenol and generate the isoprenoid precursors IPP and dimethylallyl diphosphate (DMAPP). Furthermore, IPKs have garnered attention for their impressive substrate promiscuity toward non-natural alkyl-monophosphates (alkyl-Ps), which has prompted their utilization as biocatalysts for the generation of novel isoprenoids.

A YoeB toxin cleaves both RNA and DNA.

Type II toxin-antitoxin systems contain a toxin protein, which mediates diverse interactions within the bacterial cell when it is not bound by its cognate antitoxin protein. These toxins provide a rich source of evolutionarily-conserved tertiary folds that mediate diverse catalytic reactions. These properties make toxins of interest in biotechnology applications, and studies of the catalytic mechanisms continue to provide surprises.

Bacterial Growth Mindset: Structural Plasticity in Defense Systems.

In this issue of Structure, Bertelsen et al. determine the three-dimensional structures of the Haemophilus influenzae VapD toxin, a Cas-2 homolog, with and without its cognate neutralizing antitoxin, VapX, that together comprise a toxin-antitoxin system. These reveal a unique stoichiometry, with two VapD toxins neutralized simultaneously by one VapX antitoxin.

Lifestyle Factors and Other Influences on Medical Students Choosing a Career in Emergency Medicine.

Objective: The purpose of this study was to determine which lifestyle factors influence medical students who choose a career in emergency medicine (EM).

Methods: Final-year medical students from 10 medical schools were surveyed after the National Residency Match Program match but prior to graduation regarding preferred medical specialty and lifestyle preferences. Responses from students pursuing EM regarding importance of lifestyle factors were compared to students interested in other specialties.

Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems.

The diversity of Type-II toxin-antitoxin (TA) systems in bacterial genomes requires tightly controlled interaction specificity to ensure protection of the cell, and potentially to limit cross-talk between toxin-antitoxin pairs of the same family of TA systems. Further, there is a redundant use of toxin folds for different cellular targets and complexation with different classes of antitoxins, increasing the apparent requirement for the insulation of interactions. The presence of Type II TA systems has remained enigmatic with respect to potential benefits imparted to the host cells.

Identifying a Molecular Mechanism That Imparts Species-Specific Toxicity to YoeB Toxins.

The ribosome-dependent (Ec) mRNase toxin YoeB has been demonstrated to protect cells during thermal stress. (At), a plant pathogen, also encodes a YoeB toxin. Initial studies indicated that AtYoeB does not impact the growth of Ec, but its expression is toxic to the native host At.

Inhibitor design to target a unique feature in the folate pocket of Staphylococcus aureus dihydrofolate reductase.

Staphylococcus aureus (Sa) is a serious concern due to increasing resistance to antibiotics. The bacterial dihydrofolate reductase enzyme is effectively inhibited by trimethoprim, a compound with antibacterial activity. Previously, we reported a trimethoprim derivative containing an acryloyl linker and a dihydophthalazine moiety demonstrating increased potency against S.

Reproductive rights on the path of liberation: from deconstructing the concept of control in our society to emphasizing pro-attachment attitudes.

The debate about abortion is recurrently pervading not only politics and public health but also society at large, even within the utilization of mass media. The authors reinforce that access to reproductive health is a human rights issue and discuss facts and misconceptions associated with the procedure. They reframe the discussion and scripts sometimes found in pop culture, illuminating how attitudes towards reproductive rights may affect people.

Specialty and Lifestyle Preference Changes during Medical School.

Purpose: Medical student specialty choices have significant downstream effects on the availability of physicians and, ultimately, the effectiveness of health systems. This study investigated how medical student specialty preferences change over time in relation to their demographics and lifestyle preferences.

Method: Students from ten medical schools were surveyed at matriculation (2012) and graduation (2016).

Expression of different ParE toxins results in conserved phenotypes with distinguishable classes of toxicity.

Toxin-antitoxin (TA) systems are found on both chromosomes and plasmids. These systems are unique in that they can confer both fatal and protective effects on bacterial cells-a quality that could potentially be harnessed given further understanding of these TA mechanisms. The current work focuses on the ParE subfamily, which is found throughout proteobacteria and has a sequence identity on average of approximately 12% (similarity at 30%-80%).

The toxin from a ParDE toxin-antitoxin system found in Pseudomonas aeruginosa offers protection to cells challenged with anti-gyrase antibiotics.

Toxin-antitoxin systems are mediators of diverse activities in bacterial physiology. For the ParE-type toxins, their reported role of gyrase inhibition utilized during plasmid-segregation killing indicates they are toxic. However, their location throughout chromosomes leads to questions about function, including potential non-toxic outcomes.

Treatment of Depression in Women.

Women are more likely than men to experience depression throughout the life span. Sex differences in neurochemistry and brain structure, as well as societal factors may contribute to women's increased likelihood of depression. Pharmacological research targeting depression has historically excluded women, leading to a knowledge gap regarding effective antidepressant treatment in women.

Residents Perceive Limited Education on Family Planning and Contraception for Patients with Severe and Persistent Mental Illness.

Objective: The primary goal of this study was to assess perceived adequacy of training by residents from multiple specialties on contraceptive prescribing and family planning for patients with severe and persistent mental illness (SPMI). Secondary goals included the following: (1) explore resident knowledge, attitudes, and behavior towards patients with SPMI and (2) identify barriers to meeting the reproductive health needs of patients with SPMI.

Methods: The target population was 44,237 residents from four medical specialties.

Parallel adaptive evolution of geographically distant herring populations on both sides of the North Atlantic Ocean.

Atlantic herring is an excellent species for studying the genetic basis of adaptation in geographically distant populations because of its characteristically large population sizes and low genetic drift. In this study we compared whole-genome resequencing data of Atlantic herring populations from both sides of the Atlantic Ocean. An important finding was the very low degree of genetic differentiation among geographically distant populations (fixation index = 0.

Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways.

Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module functions, but significant gaps remain about the molecular details of activation via antitoxin degradation used by different bacteria and in different environments. This review summarizes the current state of knowledge about the interaction of antitoxins with cellular proteases Lon and ClpP to mediate TA module activation.

Evaluation of New Dihydrophthalazine-Appended 2,4-Diaminopyrimidines against Bacillus anthracis: Improved Syntheses Using a New Pincer Complex.

The synthesis and evaluation of ten new dihydrophthalazine-appended 2,4-diaminopyrimidines as potential drugs to treat Bacillus anthracis is reported. An improved synthesis utilizing a new pincer catalyst, dichlorobis[1-(dicyclohexylphosphanyl)-piperidine]palladium(II), allows the final Heck coupling to be performed at 90 °C using triethylamine as the base. These milder conditions have been used to achieve improved yields for new and previously reported substrates with functional groups that degrade or react at the normal 140 °C reaction temperature.

Estimation of laceration length by emergency department personnel.

Introduction: Documentation and billing for laceration repair involves a description of wound length. We designed this study to test the hypothesis that emergency department (ED) personnel can accurately estimate wound lengths without the aid of a measuring device.

Methods: This was a single-center prospective observational study performed in an academic ED.

Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis.

The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a-b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 vs CH3) on the central ring oxygen atoms (R(2) and R(3)) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19 b and 20a-b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.

Injectable lidocaine provides similar analgesia compared to transdermal lidocaine/tetracaine patch for the incision and drainage of skin abscesses: a randomized, controlled trial.

Background: Local anesthesia used for incision and drainage of abscesses is known to be painful.

Study Objective: We studied the analgesia provided by a lidocaine/tetracaine patch compared to injectable lidocaine during incision and drainage (I&D) of skin abscesses.

Methods: This was a prospective, double-blind, randomized, controlled trial carried out in the Emergency Department (ED) of an adult tertiary referral center.