A Gram-negative-selective antibiotic that spares the gut microbiome.

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections1-3. There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile. The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics.

Differential gene expression in response to fungal pathogen exposure in the aquatic invertebrate, Daphnia dentifera.

While vertebrate immune systems are appreciated for their complexity and adaptability, invertebrate immunity is often considered to be less complex. However, immune responses in many invertebrates likely involve sophisticated processes. Interactions between the crustacean host Daphnia dentifera and its fungal pathogen Metschnikowia bicuspidata provide an excellent model for exploring the mechanisms underlying crustacean immunity. To explore the genomic basis of immunity in Daphnia, we used RNA-sequencing technology to quantify differential gene expression between individuals of a single host genotype exposed or unexposed to M. bicuspidata over 24 h. Transcriptomic analyses showed that the number of differentially expressed genes between the control (unexposed) and experimental (exposed) groups increased over time. Gene ontology enrichment analysis revealed that differentially expressed genes were enriched for immune-related molecules and processes, such as cuticle development, prostaglandin, and defense response processes. Our findings provide a suite of immunologically relevant genes and suggest the presence of a rapidly upregulated immune response involving the cuticle in Daphnia. Studies involving gene expression responses to pathogen exposure shine a light on the processes occurring during the course of infection. By leveraging knowledge on the genetic basis for immunity, immune mechanisms can be more thoroughly understood to refine our understanding of disease spread within invertebrate populations.

Homemade bread: Repurposing an ancient technology for in vitro tissue engineering.

Numerous biomaterial scaffolds have been developed which provide architectures to support the proliferation of mammalian cells. Scaffolds derived from plant components have been utilized in several tissue engineering applications, including the production of cultured meats. Bread crumb is a common ingredient employed as a texturizer and filler in existing manufacturing processes for the production of animal meat products. Though an unconventional choice as a scaffolding material, we developed a yeast-free "soda bread" with controllable porosity and mechanical properties which is stable over several weeks in culture with fibroblasts, myoblasts and pre-osteoblasts. All cells were able to proliferate throughout the three-dimensional scaffolds, depositing extra-cellular matrix while exhibiting low stress and high viability. Importantly, myoblasts were also able to differentiate into myotubes, a key step required for the culture of skeletal muscle tissue. The results suggest opportunities for the dual-use possibility of utilizing existing texturizer and filler components in future lab grown meat products, however this will of course require further validation. Regardless, the bread-derived scaffolds presented here are simply produced, inherently edible and support muscle tissue engineering, qualities which highlight their utility in the production of future meat products.

Microwave-assisted synthesis of NaMnF3 particles with tuneable morphologies.

Here, the synthesis of sub-micron MMnF3 (M = Na or K) particles by a rapid microwave-assisted approach is reported. Adjustment of the Na+-to-Mn2+ ratio in the reaction mixture yielded tuneable morphologies, i.e., rods, ribbons, and plates. Relaxometric results indicated that poly(acrylic acid)-capped MMnF3 particles exhibited characteristic magnetic properties, which endows them with potential T1-weighted contrast agent capabilities.

Using a multiple-delivery-mode training approach to develop local capacity and infrastructure for advanced bioinformatics in Africa.

With more microbiome studies being conducted by African-based research groups, there is an increasing demand for knowledge and skills in the design and analysis of microbiome studies and data. However, high-quality bioinformatics courses are often impeded by differences in computational environments, complicated software stacks, numerous dependencies, and versions of bioinformatics tools along with a lack of local computational infrastructure and expertise. To address this, H3ABioNet developed a 16S rRNA Microbiome Intermediate Bioinformatics Training course, extending its remote classroom model. The course was developed alongside experienced microbiome researchers, bioinformaticians, and systems administrators, who identified key topics to address. Development of containerised workflows has previously been undertaken by H3ABioNet, and Singularity containers were used here to enable the deployment of a standard replicable software stack across different hosting sites. The pilot ran successfully in 2019 across 23 sites registered in 11 African countries, with more than 200 participants formally enrolled and 106 volunteer staff for onsite support. The pulling, running, and testing of the containers, software, and analyses on various clusters were performed prior to the start of the course by hosting classrooms. The containers allowed the replication of analyses and results across all participating classrooms running a cluster and remained available posttraining ensuring analyses could be repeated on real data. Participants thus received the opportunity to analyse their own data, while local staff were trained and supported by experienced experts, increasing local capacity for ongoing research support. This provides a model for delivering topic-specific bioinformatics courses across Africa and other remote/low-resourced regions which overcomes barriers such as inadequate infrastructures, geographical distance, and access to expertise and educational materials.

Genome biology of the paleotetraploid perennial biomass crop Miscanthus.

Miscanthus is a perennial wild grass that is of global importance for paper production, roofing, horticultural plantings, and an emerging highly productive temperate biomass crop. We report a chromosome-scale assembly of the paleotetraploid M. sinensis genome, providing a resource for Miscanthus that links its chromosomes to the related diploid Sorghum and complex polyploid sugarcanes. The asymmetric distribution of transposons across the two homoeologous subgenomes proves Miscanthus paleo-allotetraploidy and identifies several balanced reciprocal homoeologous exchanges. Analysis of M. sinensis and M. sacchariflorus populations demonstrates extensive interspecific admixture and hybridization, and documents the origin of the highly productive triploid bioenergy crop M. × giganteus. Transcriptional profiling of leaves, stem, and rhizomes over growing seasons provides insight into rhizome development and nutrient recycling, processes critical for sustainable biomass accumulation in a perennial temperate grass. The Miscanthus genome expands the power of comparative genomics to understand traits of importance to Andropogoneae grasses.

The Effect of Sterically Active Ligand Substituents on Gas Adsorption within a Family of 3D Zn-Based Coordination Polymers.

An investigation of the adsorption properties of two structurally related, 3D coordination polymers of composition Zn(2-Mehba) and Zn(2,6-Me2hba) (2-Mehba = the dianion of 2-methyl-4-hydroxybenzoic acid and 2,6-Me2hba = the dianion of 2,6-dimethyl-4-hydroxybenzoic acid) is presented. A common feature of these structures are parallel channels that are able to accommodate appropriately sized guest molecules. The structures differ with respect to the steric congestion within the channels arising from methyl groups appended to the bridging ligands of the network. The host network, Zn(2-Mehba), is able to take up appreciable quantities of H2 (77 K) and CO2 and CH4 (298 K) in a reversible manner. In regard to the adsorption of N2 by Zn(2-Mehba), there appears to be an unusual temperature dependence for the uptake of the gas such that when the temperature is increased from 77 to 298 K the uptake of N2 increases. The relatively narrow channels of Zn(2,6-Me2hba) are too small to allow the uptake of N2 and CH4, but H2 molecules can be adsorbed. A pronounced step at elevated pressures in CO2 and N2O isotherms for Zn(2,6-Me2hba) is noted. Calculations indicate that rotation of phenolate rings leads to a change in the available intraframework space during CO2 dosing.

Field pathogenomics of Fusarium head blight reveals pathogen transcriptome differences due to host resistance.

Fusarium head blight (FHB), caused by Fusarium graminearum and other Fusarium species, is a detrimental disease that affects small grains such as wheat around the world. Management of FHB is difficult, and surveillance as well as a better understanding of pathogen aggressiveness is needed for improved control. F. graminearum disease severity varies depending on the resistance of the host genotype. In this study, we used the field pathogenomics method to investigate gene expression and population structure of isolates collected from wheat lines of varying resistance levels (susceptible, intermediate, and resistant) as well as an axenic control. Differential gene expression was found among isolates collected from different host genotypes. Candidate gene sets were identified for both F. graminearum infection of specific host genotypes and general infection to wheat. Population structure of isolates from different resistance level sources was the same, with all isolates belonging to the NA1 population.

Sequencing Framework for the Sensitive Detection and Precise Mapping of Defective Interfering Particle-Associated Deletions across Influenza A and B Viruses.

The mechanisms and consequences of defective interfering particle (DIP) formation during influenza virus infection remain poorly understood. The development of next-generation sequencing (NGS) technologies has made it possible to identify large numbers of DIP-associated sequences, providing a powerful tool to better understand their biological relevance. However, NGS approaches pose numerous technical challenges, including the precise identification and mapping of deletion junctions in the presence of frequent mutation and base-calling errors, and the potential for numerous experimental and computational artifacts. Here, we detail an Illumina-based sequencing framework and bioinformatics pipeline capable of generating highly accurate and reproducible profiles of DIP-associated junction sequences. We use a combination of simulated and experimental control data sets to optimize pipeline performance and demonstrate the absence of significant artifacts. Finally, we use this optimized pipeline to reveal how the patterns of DIP-associated junction formation differ between different strains and subtypes of influenza A and B viruses and to demonstrate how these data can provide insight into mechanisms of DIP formation. Overall, this work provides a detailed roadmap for high-resolution profiling and analysis of DIP-associated sequences within influenza virus populations.IMPORTANCE Influenza virus defective interfering particles (DIPs) that harbor internal deletions within their genomes occur naturally during infection in humans and during cell culture. They have been hypothesized to influence the pathogenicity of the virus; however, their specific function remains elusive. The accurate detection of DIP-associated deletion junctions is crucial for understanding DIP biology but is complicated by an array of technical issues that can bias or confound results. Here, we demonstrate a combined experimental and computational framework for detecting DIP-associated deletion junctions using next-generation sequencing (NGS). We detail how to validate pipeline performance and provide the bioinformatics pipeline for groups interested in using it. Using this optimized pipeline, we detect hundreds of distinct deletion junctions generated during infection with a diverse panel of influenza viruses and use these data to test a long-standing hypothesis concerning the molecular details of DIP formation.

Self-assembly of a Si-based cage by the formation of 24 equivalent covalent bonds.

A robust, nano-sized covalent cage, of composition, [(PhSi)6(ctc)4]6- (H6ctc = cyclotricatechylene) has been prepared in a simple reaction in good yield. The tetrahedral anionic cage is stable in both the solid and solution state and exhibits an affinity for Cs+ ions which bind to the internal surface of the cage.

Worm-to-Sphere Shape Transition of Thermoresponsive Linear Molecular Bottlebrushes in Moderately Concentrated Aqueous Solution.

Molecular bottlebrushes have been shown to exhibit intriguing worm-to-sphere shape transitions in response to external stimuli. However, such shape changing has been restricted to dilute solutions, typically <1.0 mg/g, or at interfaces. Here we report a method for achieving worm-to-sphere shape transitions of linear molecular bottlebrushes in moderately concentrated aqueous solutions by using binary heterografted molecular brushes composed of a poly(ethylene oxide) (PEO) and a thermoresponsive polymer as side chains. The PEO was designed to be significantly longer so that the thermoresponsive side chains were well shielded by PEO to avoid intermolecular association during the lower critical solution temperature transition. To facilitate the analysis by dynamic light scattering (DLS) and atomic force microscopy (AFM), a suitable amount of cross-linkable cinnamate groups was introduced into the thermoresponsive polymer, allowing fixing of the brush shape at higher temperatures by UV irradiation. To demonstrate the effect of relative chain lengths of the two side chain polymers, three brush polymers, BMB-5k, -2k, and -750, were synthesized by grafting an alkyne end-functionalized thermoresponsive, UV-cross-linkable polymer with a DP of 43 and a PEO with a DP of 114, 45, or 17, respectively, in a molar ratio of 1:1 onto an azide-bearing backbone polymer via a copper(I)-catalyzed click reaction. While BMB-2k and -750 underwent intermolecular aggregation in water at a concentration of 10 mg/g upon heating, DLS and AFM studies showed that BMB-5k collapsed intramolecularly and transformed from a wormlike to a spherical shape at concentrations of 10 and 25 mg/g. Even at a concentration of 100 mg/g, at least 95% of brush molecules underwent a worm-to-sphere transition from AFM analysis of the UV-cross-linked BMB-5k at a higher temperature. The method reported here may enable new opportunities for potential applications of shape changing molecular brushes.

An exploration of applicant perceptions of asynchronous video MMIs in medical selection.

This article was migrated. The article was marked as recommended. Over the last two decades, technological advancements internationally have meant that the Internet has become an important medium for recruitment and selection. Consequently, there is an increased need for research that examines the effectiveness of newer technology-mediated selection methods. This exploratory research study qualitatively explored applicant perceptions of fairness of asynchronous video interviews used in medical selection. Ten undergraduate medical students participated in a pilot asynchronous multiple-mini interview and were invited to share their experiences and perceptions in a follow-up interview. The data was transcribed verbatim and analysed using template analysis, with Gilliland's (1993) organisational justice theory guiding the original template. Many of the original themes from Gilliland's model were uncovered during analysis. Additionally, some significant themes were identified that did not form part of the original template and were therefore added to the final coding template - these were specifically relating to technology, including acceptability in a medical context; technical issues and adverse impact. Overall, results suggested that participants perceived asynchronous video interviews to be a fair method of selection. However, participants thought asynchronous interviews should only be used as part of an extensive selection process and furthermore, should not replace face-to-face interviews. Findings are discussed in line with existing research of fairness perceptions and justice theory in selection ( Gilliland, 1993) and implications for research and practice are presented.

From Single-Payer to All-Payer: Why Vermont's Reform Efforts Matter to U.S. Nurses and Their Patients.

In October 2016, the State of Vermont signed an unprecedented agreement (The All-Payer Accountable Care Model) with the Federal Government to completely reform how health care is delivered and paid for in Vermont. This innovative agreement builds on sweeping 2011 legislation that set Vermont on a course towards payment reform designed to eliminate the fragmentation, overtreatment, and high costs associated with fee-for-service reimbursement. The strong emphasis on care coordination, preventative care, the patient experience, and population health ensures a crucial and growing role for nurses in this innovative environment and provides a model to inform the nation. Such state-led reform may have particular importance during the Trump administration, given the expected emphasis on state's rights and state leadership.

Complete tracheal transection following blunt trauma in a pediatric patient.

Tracheal injury from blunt trauma is a rare, life-threatening condition in pediatric patients. Rapid assessment and identification of the severity of the injury will increase the likelihood of survival. Subcutaneous emphysema, pneumomediastinum, and persistent pneumothoraces after chest tube placement should be considered in the index of suspicion for tracheal injury. Treatment for a complete tracheal transection includes rapid airway securement via endotracheal tube or tracheostomy and careful surgical repair in the operating room in conjunction with bronchoscopy.

Do images of 'watching eyes' induce behaviour that is more pro-social or more normative? A field experiment on littering.

Displaying images of eyes causes people to behave more pro-socially in a variety of contexts. However, it is unclear whether eyes work by making people universally more pro-social, or by making them more likely to conform to local norms. If the latter, images of eyes could sometimes make people less pro-social if pro-social behaviour is not the local norm. To separate these hypotheses we conducted a field experiment in which we explored whether manipulating a local descriptive norm altered the eyes effect. We recorded litter dropping decisions on a university campus in a 2 x 2 design, comparing situations with and without litter already on the ground (a manipulation of the local descriptive norm) and with and without large signs displaying images of watching eyes. We additionally recorded the number of potential human observers in the vicinity at the time of each littering decision. We observed a norm effect: the presence of litter on the ground increased littering, replicating previous findings. We also found that images of watching eyes reduced littering, although contrary to previous findings this was only when there were larger numbers of people around. With regard to our central aim, we found no evidence that litter on the ground interacted non-additively with images of eyes to induce increased littering behaviour. Our data therefore support the hypothesis that images of eyes induce more pro-social behaviour, independent of local norms. This finding has positive implications for the application of eye images in combating anti-social behaviour.

English semantic word-pair norms and a searchable Web portal for experimental stimulus creation.

As researchers explore the complexity of memory and language hierarchies, the need to expand normed stimulus databases is growing. Therefore, we present 1,808 words, paired with their features and concept-concept information, that were collected using previously established norming methods (McRae, Cree, Seidenberg, & McNorgan Behavior Research Methods 37:547-559, 2005). This database supplements existing stimuli and complements the Semantic Priming Project (Hutchison, Balota, Cortese, Neely, Niemeyer, Bengson, & Cohen-Shikora 2010). The data set includes many types of words (including nouns, verbs, adjectives, etc.), expanding on previous collections of nouns and verbs (Vinson & Vigliocco Journal of Neurolinguistics 15:317-351, 2008). We describe the relation between our and other semantic norms, as well as giving a short review of word-pair norms. The stimuli are provided in conjunction with a searchable Web portal that allows researchers to create a set of experimental stimuli without prior programming knowledge. When researchers use this new database in tandem with previous norming efforts, precise stimuli sets can be created for future research endeavors.

Attendance at a psychological support group for people with multiple sclerosis and low mood.

PURPOSE: A cognitive behavioural group promoting psychological adjustment for people with multiple sclerosis (MS) was found to reduce psychological distress. Not all those offered treatment attended the group sessions. The aims were to examine the rates of attendance and to evaluate feedback from participants. METHOD: Participants with MS and low mood were recruited to a randomized trial comparing attendance at a psychological support group with a usual care control group. The attendance at each session was determined and those who attended were compared with those who failed to attend using a Mann-Whitney U-test or chi-squared. A sample of participants completed a telephone feedback questionnaire to determine their views of the group. RESULTS: The 44 participants who attended four or more sessions were not significantly different from the 28 who attended fewer than four sessions on demographic variables, disability, self-efficacy or quality of life, but significantly fewer men attended than women (p = 0.03). Participants' feedback from the group was mainly positive, and no factors were identified associated with non-attendance. CONCLUSIONS: Men were less likely to attend group treatment sessions than women, but no other variables were associated with non-attendance. Attendance rates influence the effectiveness of interventions and reasons for non-attendance need to be determined.

A highly symmetric diamond-like assembly of cyclotricatechylene-based tetrahedral cages.

The combination of six Cu(II) centres with four cyclotricatechylene (ctc(6-)) ligands generates large (Cu(6)ctc(4))(12-) cages with the topology of the tetrahedron. The anionic tetrahedral cages are cemented together, triangular face to triangular face, by Na(+) cations together with water molecules to generate a highly symmetric diamond-like assembly (space group Fd-3m, the same as that of diamond itself) whose adamantane-like units have an iodide ion at the centre of every cyclohexane-like face.

Evaluation of an adjustment group for people with multiple sclerosis and low mood: a randomized controlled trial.

BACKGROUND: Mood problems affect many people with multiple sclerosis (MS). The aim was to evaluate the effectiveness of a group treatment based on cognitive behavioural principles. METHODS: People with MS were screened on the General Health Questionnaire 12 (GHQ-12) and Hospital Anxiety and Depression Scale (HAD). Those identified with low mood were invited to take part in a randomized trial comparing the effect of attending an adjustment group with a waiting list control. Patients allocated to the adjustment group received six 2 h group treatment sessions. Outcomes were assessed 4 and 8 months after randomization, blind to group allocation. RESULTS: Of the 311 patients identified, 221 (71%) met the criteria for low mood and 151 (68%) agreed to take part. Hierarchical regression analyses were conducted to compare the two groups, correcting for baseline mood and disability. At 4 months, group allocation alone was a significant predictor of the primary outcome measure, the GHQ-12. At 8 months, group allocation alone was no longer a significant predictor for GHQ-12 scores, but it was when baseline GHQ-12 and Guy's Neurological Disability Scale scores were controlled for. Comparison of the area under the curve revealed significant differences between the groups for GHQ-12 (p = 0.003), HAD Anxiety (p = 0.013), HAD Depression (p = 0.004), Beck Depression Inventory (p = 0.001), MS Self-efficacy (p = 0.037) and MS Impact Scale Psychological (p = 0.012). CONCLUSION: Patients receiving treatment were less distressed and had less depression and anxiety. There was some evidence of improved self-efficacy and a reduction of the impact of MS on people's lives.

Do community factors have a differential impact on the health outcomes of boys and girls? Evidence from rural Pakistan.

In countries with large gender disparities in health status, can investments in local communities mitigate the gender bias observed in intra-household resource allocations? This paper explores the evidence for gender differences in the impact of community prices and infrastructure on child nutritional outcomes. Standardized heights and weights of rural Pakistani children are used as health indicators, while community factors include wheat prices, availability of piped water, accessibility of shops and government health clinics and the quality of the closest health facilities. The results suggest that food subsidies and programmes designed to improve the access and quality of local services may reduce the impact of intra-household gender bias on child nutrition, particularly in the long run. Specifically, by increasing the affordability of staple foods, improving the access to shops and government health centres and enhancing the quality of local care, particularly (gender-neutral) prenatal care, gender gaps in health outcomes are likely to diminish.