The Streptococcus pneumoniae pezAT toxin-antitoxin system reduces β-Lactam resistance and genetic competence

13 p.-6 fig.Chromosomally encoded Type II Toxin-Antitoxin operons are ubiquitous in bacteria and archaea. Antitoxins neutralize the toxic effect of cognate Toxins by protein-protein interactions and sequestering the active residues of the Toxin. Toxins target essential bacterial processes, mostly translation and replication. However, one class apart is constituted by the PezAT pair because the PezT toxin target cell wall biosynthesis. Here, we have examined the role of the pezAT toxin-antitoxin genes in its natural host, the pathogenic bacterium Streptococcus pneumoniae. The pezAT operon on Pneumococcal Pathogenicity Island 1 was deleted from strain R6 and its phenotypic traits were compared with those of the wild type. The mutant cells formed shorter chains during exponential phase, leading to increased colony-forming units. At stationary phase, the mutant was more resilient to lysis. Importantly, the mutant exhibited higher resistance to antibiotics targeting cell walls (β-lactams), but not to antibiotics acting at other levels. In addition, the mutants also showed enhanced genetic competence. We suggest that PezAT participates in a subtle equilibrium between loss of functions (resistance to β-lactams and genetic competence) and gain of other traits (virulence).Work supported by Grants CSD2008/00013 and BIO2015-69085-REDC from the Spanish Ministry of Economy and Competitiveness.Peer reviewe

Druggability of bacterial toxins-antitoxins

53 p.-8 fig.-3 tab.Type II (proteic) toxin-antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin is generally acting as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a detention of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the advantages and the challenges that their use may found in the ‘real’ world. We present strategies to develop TAs as antibacterials under the light of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein-protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of TAs are also discussed.Research financed by the Spanish Ministry of Economy and Innovation, grant CSD-2008/00013 (INTERMODS, to M.E.).N

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

In their initial stages of discovery, prokaryotic toxin-antitoxin (TA) systems were confined to bacterial plasmids where they function to mediate the maintenance and stability of usually low- to medium-copy number plasmids through the post-segregational killing of any plasmid-free daughter cells that developed. Their eventual discovery as nearly ubiquitous and repetitive elements in bacterial chromosomes led to a wealth of knowledge and scientific debate as to their diversity and functionality in the prokaryotic lifestyle. Currently categorized into six different types designated types I–VI, type II TA systems are the best characterized. These generally comprised of two genes encoding a proteic toxin and its corresponding proteic antitoxin, respectively. Under normal growth conditions, the stable toxin is prevented from exerting its lethal effect through tight binding with the less stable antitoxin partner, forming a non-lethal TA protein complex. Besides binding with its cognate toxin, the antitoxin also plays a role in regulating the expression of the type II TA operon by binding to the operator site, thereby repressing transcription from the TA promoter. In most cases, full repression is observed in the presence of the TA complex as binding of the toxin enhances the DNA binding capability of the antitoxin. TA systems have been implicated in a gamut of prokaryotic cellular functions such as being mediators of programmed cell death as well as persistence or dormancy, biofilm formation, as defensive weapons against bacteriophage infections and as virulence factors in pathogenic bacteria. It is thus apparent that these antitoxins, as DNA-binding proteins, play an essential role in modulating the prokaryotic lifestyle whilst at the same time preventing the lethal action of the toxins under normal growth conditions, i.e., keeping the proverbial wolves at bay. In this review, we will cover the diversity and characteristics of various type II TA antitoxins. We shall also look into some interesting deviations from the canonical type II TA systems such as tripartite TA systems where the regulatory role is played by a third party protein and not the antitoxin, and a unique TA system encoding a single protein with both toxin as well as antitoxin domains.Work supported by Grants CSD2008/00013 (to ME and WTC), and BIO2015-69085-REDC and BIO2013-49148-C2-2-R (to ME) from the Spanish Ministry of Economy and Competitiveness; PRPUM grant CG011-2014 (to CCY) from the Malaysian Ministry of Higher Education.Peer reviewedPeer Reviewe

痛恨、調諷、矛盾 : \u3c理水\u3e 的神話改編

〈理水〉是魯迅《故事新編》中8 篇「故事改寫」裏的其中一篇，這篇小說 寫於1935 年11 月，即魯迅死前大概1 年。晚年的魯迅，其實已經很少寫短篇小說，筆者認為這篇小說，反映了魯迅晚年的心態：對現實的痛恨和對未來既希望又懷疑的心態。在這樣心態之下，他對古神話「大禹治水」的故事進行了改篇，以調諷和針砭的筆觸宣泄了他這位敏感的先知晚年孤獨、憤恨、矛盾的心境

A Deep Learning Framework for Traffic Data Imputation Considering Spatiotemporal Dependencies

Spatiotemporal (ST) data collected by sensors can be represented as multi-variate time series, which is a sequence of data points listed in an order of time. Despite the vast amount of useful information, the ST data usually suffer from the issue of missing or incomplete data, which also limits its applications. Imputation is one viable solution and is often used to prepossess the data for further applications. However, in practice, n practice, spatiotemporal data imputation is quite difficult due to the complexity of spatiotemporal dependencies with dynamic changes in the traffic network and is a crucial prepossessing task for further applications. Existing approaches mostly only capture the temporal dependencies in time series or static spatial dependencies. They fail to directly model the spatiotemporal dependencies, and the representation ability of the models is relatively limited.Comment: accepted at ICITE 202

Comparative transcriptomics of multidrug-resistant Acinetobacter baumannii in response to antibiotic treatments

Abstract Multidrug-resistant Acinetobacter baumannii, a major hospital-acquired pathogen, is a serious health threat and poses a great challenge to healthcare providers. Although there have been many genomic studies on the evolution and antibiotic resistance of this species, there have been very limited transcriptome studies on its responses to antibiotics. We conducted a comparative transcriptomic study on 12 strains with different growth rates and antibiotic resistance profiles, including 3 fast-growing pan-drug-resistant strains, under separate treatment with 3 antibiotics, namely amikacin, imipenem, and meropenem. We performed deep sequencing using a strand-specific RNA-sequencing protocol, and used de novo transcriptome assembly to analyze gene expression in the form of polycistronic transcripts. Our results indicated that genes associated with transposable elements generally showed higher levels of expression under antibiotic-treated conditions, and many of these transposon-associated genes have previously been linked to drug resistance. Using co-expressed transposon genes as markers, we further identified and experimentally validated two novel genes of which overexpression conferred significant increases in amikacin resistance. To the best of our knowledge, this study represents the first comparative transcriptomic analysis of multidrug-resistant A. baumannii under different antibiotic treatments, and revealed a new relationship between transposons and antibiotic resistance

Tree management and the greening of the environment in Hong Kong : a study of collaborative governance

published_or_final_versionPolitics and Public AdministrationMasterMaster of Public Administratio

Measurement of retropubic tissue thickness using intrapartum transperineal ultrasound to assess cephalopelvic disproportion

Purpose First, to describe a new method of assessing cephalopelvic disproportion by measuring the retropubic tissue thickness (RTT), and second, to determine whether RTT was associated with an eventual delivery by cesarean section. Methods Three-dimensional transperineal ultrasound scans were performed on 129 laboring nulliparous women to obtain 3-dimensional volume datasets for assessing RTT. RTT was measured off-line by three operators (A, B, and C) as the shortest distance between the capsule of the pubic symphysis and the outer border of the fetal skull. The intraoperator repeatability of operator A and the interoperator reproducibility among A, B, and C were determined. The RTT in women who were delivered by cesarean section due to failure to progress was compared to that of women who had a vaginal delivery. Results The intraoperator repeatability for RTT was 1.2 mm. The overall RTT interoperator interclass correlation was 0.97 (0.95-0.98). The RTT in women who had a spontaneous, instrumental, or cesarean delivery was 1.16±0.32 cm, 1.12±0.25 cm, and 0.94±0.25 cm, respectively. Women who were delivered by cesarean section had a significantly smaller RTT than women who had a spontaneous delivery (P=0.008). There was no statistically significant difference in RTT between patients who had a normal vaginal delivery and patients who had an instrumental delivery (P=0.990), or between those who had an instrumental delivery and those who had a cesarean delivery after the Bonferroni correction (P=0.120). Conclusion RTT can be measured with satisfactory intraoperator repeatability and interoperator reproducibility. RTT was significantly smaller in women who eventually had a cesarean delivery than in those who had a vaginal delivery

Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial

Background: Research suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD). Aims: To compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive–behavioural therapy-based psychoeducation and usual care. Method: In total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels. Results: Linear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only. Conclusions: These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms

Accuracy of hiatal hernia diagnosis in bariatric patients : preoperative endoscopy versus intraoperative reference

Background and Aim: Obesity is becoming increasingly prevalent in Asia. Bariatric surgery in the region is growing in popularity to reflect increasing demand. Hiatal hernia (HH) is common among the obese population. There is a lack of evidence comparing preoperative endoscopy against intraoperative findings as a standard of reference for HH diagnosis. Methods: This was a retrospective analysis of a bariatric procedure database from a single tertiary teaching hospital and high-volume endoscopy center. Electronic medical records were reviewed. Endoscopy results were compared to intraoperative findings, and subgroup analysis of >2 cm hernias was performed. Sensitivity, specificity, predictive values, likelihood ratios, and global diagnostic test accuracy were calculated. Results: A total of 434 patients were eligible for this study, of which HH was detected in 37 patients (prevalence rate 8.55%). Mean age was 41.51 ± 11.07 years, and body mass index was 39.37 ± 5.67 kg/m2 . Endoscopy sensitivity was 75.68% (95% confidence interval, 58.80–88.23%) and specificity 91.44% (88.24–94.00%). Positive likelihood ratio was 8.53 (6.11–12.79) and negative likelihood ratio 0.27 (0.15–0.47). Positive predictive value was 45.16% (36.27–54.38%) and negative predictive value 97.58% (95.80–98.62%). Accuracy of endoscopy for preoperative HH diagnosis was 90.09% (86.89–92.74%). Conclusion: Endoscopy can have a high diagnostic accuracy of preoperative HH diagnosis in obese Asian patients using intraoperative diagnosis as the reference standard