At present, anti-virulence drugs are being considered as potential therapeutic alternatives and/or adjuvants to currently failing antibiotics. These drugs do not kill bacteria but inhibit virulence ...factors essential for establishing infection and pathogenesis through targeting non-essential metabolic pathways reducing the selective pressure to develop resistance. We investigated the effect of naturally isolated plant compounds on the repression of the quorum sensing (QS) system which is linked to virulence/pathogenicity in
Pseudomonas aeruginosa
. Our results show that
trans
-cinnamaldehyde (CA) and salicylic acid (SA) significantly inhibit expression of QS regulatory and virulence genes in
P. aeruginosa
PAO1 at sub-inhibitory levels without any bactericidal effect. CA effectively downregulated both the
las
and
rhl
QS systems with
lasI
and
lasR
levels inhibited by 13- and 7-fold respectively compared to 3- and 2-fold reductions with SA treatment, during the stationary growth phase. The QS inhibitors (QSI) also reduced the production of extracellular virulence factors with CA reducing protease, elastase and pyocyanin by 65%, 22% and 32%, respectively. The QSIs significantly reduced biofilm formation and concomitantly with repressed rhamnolipid gene expression, only trace amount of extracellular rhamnolipids were detected. The QSIs did not completely inhibit virulence factor expression and production but their administration significantly lowered the virulence phenotypes at both the transcriptional and extracellular levels. This study shows the significant inhibitory effect of natural plant-derived compounds on the repression of QS systems in
P. aeruginosa
.
Enterococci are robust gram-positive bacteria that are found in a variety of surroundings and that cause a significant number of healthcare-associated infections. The genus possesses a ...high-efficiency pheromone-responsive plasmid (PRP) transfer system for genetic exchange that allows antimicrobial-resistance determinants to spread within bacterial populations. The pCF10 plasmid system is the best characterised, and although other PRP systems are structurally similar, they lack exact functional homologues of pCF10-encoded genes. In this review, we provide an overview of the enterococcal PRP systems, incorporating functional details for the less-well-defined systems. We catalogue the virulence-associated elements of the PRPs that have been identified to date, and we argue that this reinforces the requirement for elucidation of the less studied systems.
Enterococci, which are on the WHO list of priority pathogens, are commonly encountered in hospital acquired infection and are becoming increasing significant due to the development of strains ...resistant to multiple antibiotics. Enterococci are also important microorganisms in the environment, and their presence is frequently used as an indicator of faecal pollution. Their success is related to their ability to survive within a broad range of habitats and the ease by which they acquire mobile genetic elements, including plasmids, from other bacteria. The enterococci are frequently present within a bacterial biofilm, which provides stability and protection to the bacterial population along with an opportunity for a variety of bacterial interactions. Enterococci can accept extrachromosomal DNA both from within its own species and from other bacterial species, and this is enhanced by the proximity of the donor and recipient strains. It is this exchange of genetic material that makes the role of biofilms such an important aspect of the success of enterococci. There remain many questions regarding the most suitable model systems to study enterococci in biofilms and regarding the transfer of genetic material including antibiotic resistance in these biofilms. This review focuses on some important aspects of biofilm in the context of horizontal gene transfer (HGT) in enterococci.
Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene
ATP7B
. Estimates for WD population prevalence vary with 1 in 30,000 ...generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of
ATP7B
variants in a genomic sequence database. A catalogue of WD-associated
ATP7B
variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated
ATP7B
variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated
ATP7B
variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some
ATP7B
variants.
A defining feature of early infancy is the immense neural plasticity that enables animals to develop a brain that is functionally integrated with a growing body. Early infancy is also defined as a ...period dominated by sleep. Here, we describe three conceptual frameworks that vary in terms of whether and how they incorporate sleep as a factor in the activity-dependent development of sensory and sensorimotor systems. The most widely accepted framework is exemplified by the visual system where retinal waves seemingly occur independent of sleep-wake states. An alternative framework is exemplified by the sensorimotor system where sensory feedback from sleep-specific movements activates the brain. We prefer a third framework that encompasses the first two but also captures the diverse ways in which sleep modulates activity-dependent development throughout the nervous system. Appreciation of the third framework will spur progress toward a more comprehensive and cohesive understanding of both typical and atypical neurodevelopment.
Infant animals spend the majority of each day asleep, but researchers are only beginning to delineate the contributions of sleep to sensory neurodevelopment. In this perspective, Blumberg et al. provide a conceptual framework to guide future progress.
Cortical development is an activity-dependent process 1–3. Regarding the role of activity in the developing somatosensory cortex, one persistent debate concerns the importance of sensory feedback ...from self-generated movements. Specifically, recent studies claim that cortical activity is generated intrinsically, independent of movement 3, 4. However, other studies claim that behavioral state moderates the relationship between movement and cortical activity 5–7. Thus, perhaps inattention to behavioral state leads to failures to detect movement-driven activity 8. Here, we resolve this issue by associating local field activity (i.e., spindle bursts) and unit activity in the barrel cortex of 5-day-old rats with whisker movements during wake and myoclonic twitches of the whiskers during active (REM) sleep. Barrel activity increased significantly within 500 ms of whisker movements, especially after twitches. Also, higher-amplitude movements were more likely to trigger barrel activity; when we controlled for movement amplitude, barrel activity was again greater after a twitch than a wake movement. We then inverted the analysis to assess the likelihood that increases in barrel activity were preceded within 500 ms by whisker movements: at least 55% of barrel activity was attributable to sensory feedback from whisker movements. Finally, when periods with and without movement were compared, 70%–75% of barrel activity was movement related. These results confirm the importance of sensory feedback from movements in driving activity in sensorimotor cortex and underscore the necessity of monitoring sleep-wake states to ensure accurate assessments of the contributions of the sensory periphery to activity in developing somatosensory cortex.
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•In newborn rats, self-generated whisker movements trigger barrel cortex activity•Larger whisker movements are more likely to trigger responses in barrel cortex•Movement-related cortical activity occurs more often during active sleep than wake•When pups don’t move at all, there is a 3-fold reduction in cortical activity
Some researchers have questioned whether sensory feedback from movements drives activity in developing somatosensory cortex. On the contrary, using infant rats, Dooley et al. establish that activity in barrel cortex depends critically on sensory feedback from whisker movements, particularly during active sleep.
Antibiotic resistant bacteria from faecal pollution sources are pervasive in aquatic environments. A facilitating role for the emergence of waterborne, multi-drug resistant bacterial pathogens has ...been attributed to biofiltration but had not yet been substantiated. This study investigated the effect of filtration and gut passage in Daphnia spp. on conjugal transfer of resistance genes in Enterococcus faecalis. In vivo conjugation experiments involved a vancomycin-resistant donor strain bearing a plasmid-borne vanA resistance gene, and two vancomycin-susceptible and rifampicin-resistant recipient strains in the presence of Daphnia magna or Daphnia pulex. Results showed successful transfer of the vanA resistance gene from donor to recipient; gene identity was confirmed by PCR and DNA sequencing. There was no significant difference in the number of transconjugants recovered from D. magna and D. pulex. However, transconjugant numbers differed by one order of magnitude between recipient strains. Transconjugant numbers from D. magna were also significantly different between treatments with ingestion of individual phytoplankton species before filtration of bacteria. The highest transfer efficiency calculated from excreted transconjugants was 2.5 × 10−6. This proof of concept for facilitation of horizontal gene transfer by a filter feeding organism provides evidence that Daphnia can disseminate antibiotic resistant transconjugants in the environment.
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•Daphnia ingested vancomycin resistant donor strains and rifampicin resistant recipient strains of Enterococcus faecalis.•There was co-resistance against both antibiotics among excreted E. faecalis.•PCR evidence supported conjugal transfer of vancomycin resistance.•Gut passage facilitated antibiotic resistance transfer.•Competence of recipient strains and presence of ingested algae affected resistance transfer efficiency.
Global climate changes during the Cenozoic (65.5–0 Ma) caused major biological range shifts and extinctions. In northern Europe, for example, a pattern of few endemics and the dominance of ...wide‐ranging species is thought to have been determined by the Pleistocene (2.59–0.01 Ma) glaciations. This study, in contrast, reveals an ancient subsurface fauna endemic to Britain and Ireland. Using a Bayesian phylogenetic approach, we found that two species of stygobitic invertebrates (genus Niphargus) have not only survived the entire Pleistocene in refugia but have persisted for at least 19.5 million years. Other Niphargus species form distinct cryptic taxa that diverged from their nearest continental relative between 5.6 and 1.0 Ma. The study also reveals an unusual biogeographical pattern in the Niphargus genus. It originated in north‐west Europe approximately 87 Ma and underwent a gradual range expansion. Phylogenetic diversity and species age are highest in north‐west Europe, suggesting resilience to extreme climate change and strongly contrasting the patterns seen in surface fauna. However, species diversity is highest in south‐east Europe, indicating that once the genus spread to these areas (approximately 25 Ma), geomorphological and climatic conditions enabled much higher diversification. Our study highlights that groundwater ecosystems provide an important contribution to biodiversity and offers insight into the interactions between biological and climatic processes.
Before primary motor cortex (M1) develops its motor functions, it functions like a somatosensory area. Here, by recording from neurons in the forelimb representation of M1 in postnatal day (P) 8-12 ...rats, we demonstrate a rapid shift in its sensory responses. At P8-10, M1 neurons respond overwhelmingly to feedback from sleep-related twitches of the forelimb, but the same neurons do not respond to wake-related movements. By P12, M1 neurons suddenly respond to wake movements, a transition that results from opening the sensory gate in the external cuneate nucleus. Also at P12, fewer M1 neurons respond to individual twitches, but the full complement of twitch-related feedback observed at P8 is unmasked through local disinhibition. Finally, through P12, M1 sensory responses originate in the deep thalamorecipient layers, not primary somatosensory cortex. These findings demonstrate that M1 initially establishes a sensory framework upon which its later-emerging role in motor control is built.
With our eyes closed, we can track a limb’s moment-to-moment location in space. If this capacity relied solely on sensory feedback from the limb, we would always be a step behind because sensory ...feedback takes time: for the execution of rapid and precise movements, such lags are not tolerable. Nervous systems solve this problem by computing representations—or internal models—that mimic movements as they are happening, with the associated neural activity occurring after the motor command but before sensory feedback. Research in adults indicates that the cerebellum is necessary to compute internal models. What is not known, however, is when—and under what conditions—this computational capacity develops. Here, taking advantage of the unique kinematic features of the discrete, spontaneous limb twitches that characterize active sleep, we captured the developmental emergence of a cerebellar-dependent internal model. Using rats at postnatal days (P) 12, P16, and P20, we compared neural activity in the ventral posterior (VP) and ventral lateral (VL) thalamic nuclei, both of which receive somatosensory input but only the latter of which receives cerebellar input. At all ages, twitch-related activity in VP lagged behind the movement, consistent with sensory processing; similar activity was observed in VL through P16. At P20, however, VL activity no longer lagged behind movement but instead precisely mimicked the movement itself; this activity depended on cerebellar input. In addition to demonstrating the emergence of internal models of movement, these findings implicate twitches in their development and calibration through, at least, the preweanling period.
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•Twitches trigger activity in thalamus and cortex beyond the early postnatal period•Twitch-related activity is spatiotemporally refined by the 3rd postnatal week•Motor thalamus activity reflects an internal model of a twitch•This internal model of movement depends on cerebellar output
Internal models of movement enable the production of coordinated behavior; however, we do not know when internal models first develop. Using myoclonic twitches, movements that are produced exclusively during sleep, Dooley et al. establish the emergence of a cerebellar-dependent internal model of movement in motor thalamus of rats at 20 days of age.
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