Synthetic studies with bacitracin A and preparation of analogues containing alternative zinc binding groups

Microbial Biotechnolog

Cognitive and psychosocial outcomes of mechanically ventilated intensive care patients with and without delirium

Abstract Objective Delirium is common in intensive care patients and is associated with short- and long-term adverse outcomes. We investigated the long-term risk of cognitive impairment and post-traumatic stress disorder (PTSD) in intensive care patients with and without delirium. Methods This is a prospective cohort study in ICUs in two Australian university-affiliated hospitals. Patients were eligible if they were older than 18 years, mechanically ventilated for more than 24 h and did not meet exclusion criteria. Delirium was assessed using the Confusion Assessment Method for Intensive Care Unit. Variables assessing cognitive function and PTSD symptoms were collected at ICU discharge, after 6 and 12 months: Mini-Mental State Examination, Telephone Interview for Cognitive Status, Impact of Events Scale-Revised and Informant Questionnaire for Cognitive Decline (caregiver). Results 103 participants were included of which 36% developed delirium in ICU. Patients with delirium were sicker and had longer duration of mechanical ventilation and ICU length of stay. After 12 months, 41/60 (68.3%) evaluable patients were cognitively impaired, with 11.6% representing the presence of symptoms consistent with dementia. When evaluated by the patient’s caregiver, the patient’s cognitive function was found to be severely impaired in a larger proportion of patients (14/60, 23.3%). Delirium was associated with worse cognitive function at ICU discharge, but not with long-term cognitive function. IES-R scores, measuring PTSD symptoms, were significantly higher in patients who had delirium compared to patients without delirium. In regression analysis, delirium was independently associated with cognitive function at ICU discharge and PTSD symptoms at 12 months. Conclusions Intensive care survivors have significant rates of long-term cognitive decline and PTSD symptoms. Delirium in ICU was independently associated with short-term but not long-term cognitive function, and with long-term PTSD symptoms. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12616001116415, 15/8/2016 retrospectively registered, https://www.anzctr.org.a

Do plant species influence soil CO2 and N2O fluxes in a diverse tropical forest?

To test whether plant species influence greenhouse gas production in diverse ecosystems, we measured wet season soil CO2 and N2O fluxes close to ~300 large (>35 cm in diameter at breast height (DBH)) trees of 15 species at three clay-rich forest sites in central Amazonia. We found that soil CO2 fluxes were 38% higher near large trees than at control sites >10 m away from any tree (P < 0.0001). After adjusting for large tree presence, a multiple linear regression of soil temperature, bulk density, and liana DBH explained 19% of remaining CO2 flux variability. Soil N2O fluxes adjacent to Caryocar villosum, Lecythis lurida, Schefflera morototoni, and Manilkara huberi were 84%-196% greater than Erisma uncinatum and Vochysia maxima, both Vochysiaceae. Tree species identity was the most important explanatory factor for N2O fluxes, accounting for more than twice the N2O flux variability as all other factors combined. Two observations suggest a mechanism for this finding: (1) sugar addition increased N2O fluxes near C. villosum twice as much (P < 0.05) as near Vochysiaceae and (2) species mean N2O fluxes were strongly negatively correlated with tree growth rate (P = 0.002). These observations imply that through enhanced belowground carbon allocation liana and tree species can stimulate soil CO2 and N2O fluxes (by enhancing denitrification when carbon limits microbial metabolism). Alternatively, low N2O fluxes potentially result from strong competition of tree species with microbes for nutrients. Species-specific patterns in CO2 and N2O fluxes demonstrate that plant species can influence soil biogeochemical processes in a diverse tropical forest

The distribution of deep-sea sponge aggregations (Porifera) in relation to oceanographic processes in the Faroe-Shetland Channel.

Deep-sea sponge aggregations have been identified as potential Vulnerable Marine Ecosystems under United Nations General Assembly Resolution 61/105. Understanding the distribution of these habitats is critical to future spatial management efforts, and central to this understanding are quantitative data on the environmental drivers of that distribution. Accumulations of large suspension feeders are hypothesised to aggregate in regions of internal wave formation. The causal link is thought to be an increase in the supply of food related to the incidence of internal waves, which results in resuspension of particulate organic matter on which the sponges feed. There is, however, almost no empirical evidence to support this hypothesis for deep-sea sponge aggregations, although there is strong circumstantial evidence. We tested the relationship between sponge density and 1) temperature range (as a measure of internal wave presence in this region), and 2) optical backscatter (a measure of particulate flux) for a known sponge aggregation in the Faroe-Shetland Channel where internal wave interaction with the slope is further well-documented. 25 benthic video transects, ranging from 422 to 979 m water depth were conducted in the study region. 225 images were analysed and all taxa identified to morphotypes and quantified. Temperature and optical backscatter data were drawn from archived CTD data, and data from long term (4 months) and 2 seasonal short term (11 days) mooring deployments from the region. A generalised linear model was used to test the relationship between sponge density and temperature range (ΔT), and sponge density and optical backscatter. The results showed a statistically significant positive relationship between sponge density and temperature range, with the highest sponge densities occurring at depths of greatest temperature range. They showed a statistically significant positive relationship between sponge density and optical backscatter for long term and one short term seasonal deployment (Sep–Oct), but a weak negative relationship for the other short term mooring deployment (April-May). We conclude that sponge aggregations in the Faroe-Shetland Channel are associated with slope regions that are subjected to abrupt and pronounced changes in temperature due to intensified internal wave activity over the slope between depths of 400–600 and that lead to intensified near-bed currents and elevated resuspension of particulate. Our data provide empirical evidence of the relationship between internal wave processes and deep-sea sponge aggregations. These data modify current theory on drivers of deep sea sponge aggregation distribution, suggesting aggregations also occur directly within regions of internal wave breaking, rather than simply proximal to these regions

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) for adults with Autism Spectrum Disorder:A feasibility study

Background: Social cognitive difficulties in Autism Spectrum Disorder (ASD) can affect the daily lives of people with ASD profoundly, impacting the development and maintenance of meaningful social relations. Social cognition training (SCT) is commonly used for improving social functioning, but lacks ecological validity and the ability to effectively mimic social situations. Development of virtual reality (VR) interventions, focusing on enhancing social cognition, could add to the effectiveness of SCT within ASD care, by offering a safe, interactive and practical training setting, where generalization of knowledge and skills to the real-world are promoted. In this paper, our primary aim is to evaluate the feasibility and acceptance by participants and therapists of the Dynamic Interactive Social Cognition Method: Training in Virtual Reality (DiSCoVR) protocol as developed for adults with schizophrenic spectrum disorder (SSD), adapted for ASD (DiSCoVR-A). 26 participants, aged 18-63, took part in a pilot study. 22 participants completed baseline and post-assessment, including primary outcome evaluation assessment through a semi-structured interview. Secondary measures focused on social cognition, emotion recognition, mental flexibility, social anxiety, empathy and social responsiveness and were assessed at baseline (T0), post-treatment (T1), and at follow-up (T2) sixteen weeks after completion of the intervention. Results: Our results show that the majority of participant and therapists found the VR intervention acceptable and feasible, as reported in evaluation questionnaires and interviews. Conclusion: These preliminary findings are promising; however, controlled research is needed to further investigate the effectiveness of VR within social cognition training for adults with ASD

Cephalosporin prodrug inhibitors overcome metallo-β-lactamase driven antibiotic resistance

Microbial Biotechnolog

Mechanistic investigations of metallo-β-lactamase inhibitors: strong zinc binding is not required for potent enzyme inhibition

Microbial Biotechnolog

BCG as a case study for precision vaccine development: lessons from vaccine heterogeneity, trained immunity, and immune ontogeny

Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces “heterologous” protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed “trained immunity.” In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TB-specific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG’s innate immune activation, suggesting that aspects of BCG’s effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines

Dexamethasone in osteogenic medium strongly induces adipocyte differentiation of mouse bone marrow stromal cells and increases osteoblast differentiation

BACKGROUND: Osteoblasts and adipocytes share a common mesenchymal stem cell origin. Therefore, it has been suggested that the accumulation of marrow adipocytes observed in bone loss is caused by a shift in the commitment of mesenchymal stem cells from the osteogenic pathway to the adipogenic pathway. Supporting this hypothesis the competition between adipogenic and osteogenic lineages was widely demonstrated on partially homogeneous cell populations. However, some data from mouse models showed the existence of an independent relationship between bone mineral content and bone marrow adiposity. Therefore, the combination of adipogenesis and osteogenesis in primary culture would be helpful to determine if this competition would be observed on a whole bone marrow stromal cell population in a culture medium allowing both lineages. In this aim, mouse bone marrow stromal cells were cultured in a standard osteogenic medium added with different concentrations of Dexamethasone, known to be an important regulator of mesenchymal progenitor cell differentiation.RESULTS: Gene expression of osteoblast and adipocyte markers, biochemical and physical analyses demonstrated the presence of both cell types when Dexamethasone was used at 100 nM. Overall, our data showed that in this co-differentiation medium both differentiation lineages were enhanced compared to classical adipogenic or osteogenic culture medium. This suggests that in this model, adipocyte phenotype does not seem to increase at the expense of the osteoblast lineage.CONCLUSION: This model appears to be a promising tool to study osteoblast and adipocyte differentiation capabilities and the interactions between these two processes

Structural studies provide new insights into the role of lysine acetylation on substrate recognition by CARM1 and inform the design of potent peptidomimetic inhibitors

Microbial Biotechnolog