The role of mathematical modelling in understanding prokaryotic predation

With increasing levels of antimicrobial resistance impacting both human and animal health, novel means of treating resistant infections are urgently needed. Bacteriophages and predatory bacteria such as Bdellovibrio bacteriovorus have been proposed as suitable candidates for this role. Microbes also play a key environmental role as producers or recyclers of nutrients such as carbon and nitrogen, and predators have the capacity to be keystone species within microbial communities. To date, many studies have looked at the mechanisms of action of prokaryotic predators, their safety in in vivo models and their role and effectiveness under specific conditions. Mathematical models however allow researchers to investigate a wider range of scenarios, including aspects of predation that would be difficult, expensive, or time-consuming to investigate experimentally. We review here a history of modelling in prokaryote predation, from simple Lotka-Volterra models, through increasing levels of complexity, including multiple prey and predator species, and environmental and spatial factors. We consider how models have helped address questions around the mechanisms of action of predators and have allowed researchers to make predictions of the dynamics of predator–prey systems. We examine what models can tell us about qualitative and quantitative commonalities or differences between bacterial predators and bacteriophage or protists. We also highlight how models can address real-world situations such as the likely effectiveness of predators in removing prey species and their potential effects in shaping ecosystems. Finally, we look at research questions that are still to be addressed where models could be of benefit

The role of mathematical modelling in understanding prokaryotic predation

With increasing levels of antimicrobial resistance impacting both human and animal health, novel means of treating resistant infections are urgently needed. Bacteriophages and predatory bacteria such as Bdellovibrio bacteriovorus have been proposed as suitable candidates for this role. Microbes also play a key environmental role as producers or recyclers of nutrients such as carbon and nitrogen, and predators have the capacity to be keystone species within microbial communities. To date, many studies have looked at the mechanisms of action of prokaryotic predators, their safety in in vivo models and their role and effectiveness under specific conditions. Mathematical models however allow researchers to investigate a wider range of scenarios, including aspects of predation that would be difficult, expensive, or time-consuming to investigate experimentally. We review here a history of modelling in prokaryote predation, from simple Lotka-Volterra models, through increasing levels of complexity, including multiple prey and predator species, and environmental and spatial factors. We consider how models have helped address questions around the mechanisms of action of predators and have allowed researchers to make predictions of the dynamics of predator–prey systems. We examine what models can tell us about qualitative and quantitative commonalities or differences between bacterial predators and bacteriophage or protists. We also highlight how models can address real-world situations such as the likely effectiveness of predators in removing prey species and their potential effects in shaping ecosystems. Finally, we look at research questions that are still to be addressed where models could be of benefit

Dual predation by bacteriophage and bdellovibrio bacteriovorus can eradicate escherichia coli prey in situations where single predation cannot

Copyright © 2020 Hobley et al. Bacteria are preyed upon by diverse microbial predators, including bacteriophage and predatory bacteria, such as Bdellovibrio bacteriovorus. While bacteriophage are used as antimicrobial therapies in Eastern Europe and are being applied for compassionate use in the United States, predatory bacteria are only just beginning to reveal their potential therapeutic uses. However, predation by either predator type can falter due to different adaptations arising in the prey bacteria. When testing poultry farm wastewater for novel Bdellovibrio isolates on Escherichia coli prey lawns, individual composite plaques were isolated containing both an RTP (rosette-tailed-phage)-like-phage and a B. bacteriovorus strain and showing central prey lysis and halos of extra lysis. Combining the purified phage with a lab strain of B. bacteriovorus HD100 recapitulated haloed plaques and increased killing of the E. coli prey in liquid culture, showing an effective side-by-side action of these predators compared to their actions alone. Using approximate Bayesian computation to select the best fitting from a variety of different mathematical models demonstrated that the experimental data could be explained only by assuming the existence of three prey phenotypes: (i) sensitive to both predators, (ii) genetically resistant to phage only, and (iii) plastic resistant to B. bacteriovorus only. Although each predator reduces prey availability for the other, high phage numbers did not abolish B. bacteriovorus predation, so both predators are competent to coexist and are causing different selective pressures on the bacterial surface while, in tandem, controlling prey bacterial numbers efficiently. This suggests that combinatorial predator therapy could overcome problems of phage resistance. Importance: With increasing levels of antibiotic resistance, the development of alternative antibacterial therapies is urgently needed. Two potential alternatives are bacteriophage and predatory bacteria. Bacteriophage therapy has been used, but prey/host specificity and the rapid acquisition of bacterial resistance to bacteriophage are practical considerations. Predatory bacteria are of interest due to their broad Gram-negative bacterial prey range and the lack of simple resistance mechanisms. Here, a bacteriophage and a strain of Bdellovibrio bacteriovorus, preyed side by side on a population of E. coli, causing a significantly greater decrease in prey numbers than either alone. Such combinatorial predator therapy may have greater potential than individual predators since prey surface changes selected for by each predator do not protect prey against the other predator

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Predation strategies of the bacterium Bdellovibrio bacteriovorus result in overexploitation and bottlenecks

With increasing antimicrobial resistance, alternatives for treating infections or removing resistant bacteria are urgently needed, such as the bacterial predator Bdellovibrio bacteriovorus or bacteriophage. Therefore, we need to better understand microbial predator–prey dynamics. We developed mass-action mathematical models of predation for chemostats, which capture the low substrate concentration and slow growth typical for intended application areas of the predators such as wastewater treatment, aquaculture, or the gut. Our model predicted that predator survival required a minimal prey cell size, explaining why Bdellovibrio is much smaller than its prey. A predator considered to be “too good” (attack rate too high, mortality too low) overexploited its prey, leading to extinction (tragedy of the commons). Surprisingly, a predator taking longer to produce more offspring outcompeted a predator producing fewer offspring more rapidly (rate versus yield trade-off). Predation was only efficient in a narrow region around optimal parameters. Moreover, extreme oscillations under a wide range of conditions led to severe bottlenecks. These could be avoided when two prey species became available in alternating seasons. A bacteriophage outcompeted Bdellovibrio due to its higher burst size and faster life cycle. Together, results suggest that Bdellovibrio would struggle to survive on a single prey, explaining why it must be a generalist predator and suggesting it is better suited than phage to environments with multiple prey. IMPORTANCE The discovery of antibiotics led to a dramatic drop in deaths due to infectious disease. Increasing levels of antimicrobial resistance, however, threaten to reverse this progress. There is thus a need for alternatives, such as therapies based on phage and predatory bacteria that kill bacteria regardless of whether they are pathogens or resistant to antibiotics. To best exploit them, we need to better understand what determines their effectiveness. By using a mathematical model to study bacterial predation in realistic slow growth conditions, we found that the generalist predator Bdellovibrio is most effective within a narrow range of conditions for each prey. For example, a minimum prey cell size is required, and the predator should not be “too good,” as this would result in overexploitation risking extinction. Together these findings give insights into the ecology of microbial predation and help explain why Bdellovibrio needs to be a generalist predator

Corticospinal excitability measurements using transcranial magnetic stimulation are valid with intramuscular electromyography.

OBJECTIVES:Muscular targets that are deep or inaccessible to surface electromyography (sEMG) require intrinsic recording using fine-wire electromyography (fEMG). It is unknown if fEMG validly record cortically evoked muscle responses compared to sEMG. The purpose of this investigation was to establish the validity and agreement of fEMG compared to sEMG to quantify typical transcranial magnetic stimulation (TMS) measures pre and post repetitive TMS (rTMS). The hypotheses were that fEMG would demonstrate excellent validity and agreement compared with sEMG. MATERIALS AND METHODS:In ten healthy volunteers, paired pulse and cortical silent period (CSP) TMS measures were collected before and after 1200 pulses of 1Hz rTMS to the motor cortex. Data were simultaneously recorded with sEMG and fEMG in the first dorsal interosseous. Concurrent validity (r and rho) and agreement (Tukey mean-difference) were calculated. RESULTS:fEMG quantified corticospinal excitability with good to excellent validity compared to sEMG data at both pretest (r = 0.77-0.97) and posttest (r = 0.83-0.92). Pairwise comparisons indicated no difference between sEMG and fEMG for all outcomes; however, Tukey mean-difference plots display increased variance and questionable agreement for paired pulse outcomes. CSP displayed the highest estimates of validity and agreement. Paired pulse MEP responses recorded with fEMG displayed reduced validity, agreement and less sensitivity to changes in MEP amplitude compared to sEMG. Change scores following rTMS were not significantly different between sEMG and fEMG. CONCLUSION:fEMG electrodes are a valid means to measure CSP and paired pulse MEP responses. CSP displays the highest validity estimates, while caution is warranted when assessing paired pulse responses with fEMG. Corticospinal excitability and neuromodulatory aftereffects from rTMS may be assessed using fEMG

Simultaneous surface and fine-wire EMG trace.

<p>Example of a single pulse motor evoked potential response in a single subject.</p

Cerebellar Transcranial Direct Current Stimulation Modulates Corticospinal Excitability During Motor Training

Background: Cerebellar activity can be modulated using cerebellar transcranial direct current stimulation (ctDCS) and, when applied concurrently with task training, has been shown to facilitate cognitive and motor performance. However, how ctDCS facilitates motor performance is not fully understood.Objective/Hypothesis: To assess the electrophysiological and motor performance effects of ctDCS applied during motor training.Methods: Fourteen healthy adults (age 28.8 ± 10.5 years) were randomly assigned to complete one session of finger tracking training with either simultaneous bilateral anodal or sham ctDCS. Training was completed in two 15 min epochs with a 5-min break (total 30 min stimulation, 2 mA). Tracking accuracy and corticospinal and intracortical excitability were measured immediately before and after the training period. Motor cortical excitability measures included resting motor threshold (RMT), motor evoked potential (MEP) amplitude, cortical silent period (CSP) and short interval intracortical inhibition (SICI).Results: There was a significant interaction of Group * Time for MEP amplitude and CSP duration (p &lt; 0.01). Post hoc analysis revealed MEP amplitude was increased in the sham group (p &lt; 0.01), indicating increased corticospinal excitability from baseline while the anodal group displayed a decrease in MEP amplitude (p = 0.023) and prolongation of CSP duration (p &lt; 0.01). SICI and RMT remained unchanged following ctDCS and training. Task accuracy was improved in both groups at post-test with a significant effect of Time (p &lt; 0.01); however, there was no effect of Group (p = 0.45) or interaction of Group * Time (p = 0.83). During training, there was a significant effect of Block (p &lt; 0.01) but no significant effect of Group or interaction effect (p &gt; 0.06).Conclusions: ctDCS applied during task training is capable of modulating or interfering with practice-related changes in corticospinal excitability without disrupting performance improvement