Multiscale simulations identify origins of differential carbapenem hydrolysis by the OXA-48 β-lactamase

OXA-48 β-lactamases are frequently encountered in bacterial infections caused by carbapenem-resistant Gram-negative bacteria. Due to the importance of carbapenems in treatment of healthcare-associated infections, and the increasingly wide dissemination of OXA-48-like enzymes on plasmids, these β-lactamases are of high clinical significance. Notably, OXA-48 hydrolyses imipenem more efficiently than other commonly used carbapenems, such as meropenem. Here, we use extensive multi-scale simulations of imipenem and meropenem hydrolysis by OXA-48 to dissect the dynamics and to explore differences in reactivity of the possible conformational substates of the respective acylenzymes. QM/MM simulations of the deacylation reaction for both substrates demonstrate that deacylation is favoured when the 6α-hydroxyethyl group is able to hydrogen bond to the water molecule responsible for deacylation, but disfavoured by increasing hydration of either oxygen of the carboxylated Lys73 general base. Differences in free energy barriers calculated from the QM/MM simulations correlate well with the experimentally observed differences in hydrolytic efficiency between meropenem and imipenem. We conclude that the impaired breakdown of meropenem, compared to imipenem, which arises from a subtle change in the hydrogen bonding pattern between the deacylating water molecule and the antibiotic, is most likely induced by the meropenem 1-methyl group. In addition to increased insights into carbapenem breakdown by OXA β-lactamases, which may aid design of new antibiotics or inhibitors, our approach exemplifies the combined use of atomistic simulations in determining the possible different enzyme-substrate substates, and their influence on enzyme reaction kinetics.

Identifying individuals with recent COVID-19 through voice classification using deep learning

Recently deep learning has attained a breakthrough in model accuracy for the classification of images due mainly to convolutional neural networks. In the present study, we attempted to investigate the presence of subclinical voice feature alteration in COVID-19 patients after the recent resolution of disease using deep learning. The study was a prospective study of 76 post COVID-19 patients and 40 healthy individuals. The diagnoses of post COVID-19 patients were based on more than the eighth week after onset of symptoms. Voice samples of an ‘ah’ sound, coughing sound and a polysyllabic sentence were collected and preprocessed to log-mel spectrogram. Transfer learning using the VGG19 pre-trained convolutional neural network was performed with all voice samples. The performance of the model using the polysyllabic sentence yielded the highest classification performance of all models. The coughing sound produced the lowest classification performance while the ability of the monosyllabic ‘ah’ sound to predict the recent COVID-19 fell between the other two vocalizations. The model using the polysyllabic sentence achieved 85% accuracy, 89% sensitivity, and 77% specificity. In conclusion, deep learning is able to detect the subtle change in voice features of COVID-19 patients after recent resolution of the disease.

MISTAKE AND SURETYSHIP: AVOIDING THE SPECTRE OF BRINK V HUMPHRIES & JEWELL (PTY) LTD

The nettlesome matter of operative mistake and suretyships tucked away in credit applications tends to find its way into the law reports on a rather frequent basis. This phenomenon is hardly surprising because in the cut and thrust of modern commerce, and even more so in lean times, individuals are keen to apply for credit on behalf of the corporate entities which they represent, but less eager to stand in for these debts when they cannot be serviced. From the contractual perspective of mistake, these cases tend tofollow a familiar pattern. Commonly, a member of a close corporation or director of a private company applies on behalf of the close corporation or company, as the case may be, for some or other form of credit from another party. Usually, within a business context, credit will not be granted without some form of security, and in these instances more often than not the representative is required to agree to a personal suretyship in favour of the creditor, which is often embodied in the credit application form itself. Oncethe representative has appended him or her signature to the application form, he or she inexorably finds himself or herself simultaneously bound as surety and co-principal debtor, the formal requirements for a suretyship agreement having been complied with (as prescribed by s 6 of the General Law Amendment Act 50 of 1956). On the whole older case law displays a reluctancy on the part of the judiciary to excuse a surety on the basis of material mistake in such circumstances, but in Brink v Humphries & Jewell (Pty) Ltd (2005 2 SA 419 (SCA)) the Supreme Court of Appeal adopted a far more lenient approach in favour of the surety, and perhaps heralded a not too subtle change in the law. This note examines the way in which the courts have adjudicated similar cases, and specifically whether more recently they have reinforced the generally stricter approach of old or been prepared to follow the path which Brink seemed to have cleared.

On the molecular origins of the ferroelectric splay nematic phase

Nematic liquid crystals have been known for more than a century, but it was not until the 60s–70s that, with the development of room temperature nematics, they became widely used in applications. Polar nematic phases have been long-time predicted, but have only been experimentally realized recently. Synthesis of materials with nematic polar ordering at room temperature is certainly challenging and requires a deep understanding of its formation mechanisms, presently lacking. Here, we compare two materials of similar chemical structure and demonstrate that just a subtle change in the molecular structure enables denser packing of the molecules when they exhibit polar order, which shows that reduction of excluded volume is in the origin of the polar nematic phase. Additionally, we propose that molecular dynamics simulations are potent tools for molecular design in order to predict, identify and design materials showing the polar nematic phase and its precursor nematic phases.

Detecting the Vegetation Change Related to the Creep of 2018 Baige Landslide in Jinsha River, SE Tibet Using SPOT Data

It is vital to monitor the post-seismic landslides economically and effectively in high-mountain regions for the long term. The landslide creep could cause a subtle change of the overlying vegetation after the earthquake, which will lead to the change of vegetation spectral characteristics in optical remote sensing data. The optical remote sensing technique can be used to monitor the landslide creep areas with dense vegetation in a large range at a low cost because it is easy to obtain multi-temporal, multiple-scale, and multi-spectral information. We identified and extracted the vegetation change area before the 2018 Baige landslide by the high-resolution optical remote sensing data. Firstly, the image fusion method was used to improve the accuracy of change detection. Then, vegetation coverage before the landslide was calculated. The vegetation change was identified, and qualitative and quantitative methods were used to analyze the spatio-temporal changes of vegetation coverage. Our results indicate that the creep distance of the landslide is about 50 m and the vegetation in the back scarp area and the main sliding area display a significant downward trend with time closing to the landslide comparing with that in the reference area. The vegetation change in the remote sensing image has an excellent spatio-temporal correlation with the landslide creep. This study provides a possible way and perspective for monitoring post-seismic landslide disasters.

Turkey will upgrade Ukraine partnership cautiously

Significance The relationship is shaped and moderated by Turkey's mix of cooperation and competition with Moscow. Ankara will not use Ukraine as an arena for challenging Russia openly, but its more active engagement signals a subtle change in approach. Impacts Simultaneous NATO and Russian naval exercises create scope for heightened friction. Turkey will explore greater security cooperation with Georgia as well as Azerbaijan. Ankara will also build on previous growth in relations with Moldova.

P–280 Changes in oolemma height during ICSI injection on day 0 is associated with day 5–6 blastocyst formation

Study question Does the oolemma response to ICSI injection on day 0 affect blastocyst formation on day 5–6 (d5/6)? Summary answer A large change in oolemma height during ICSI injection on day 0 is associated with lower blastocyst formation rates on d5/6. What is known already The oolemma changes in all dimensions (i.e. height, width and depth) and can exhibit different reactions in ICSI during needle injection. This is seen as instant rupture or with little needle pressure, normal rupture with the needle pushed approximately halfway through, or difficult rupture with repeated attempts or the needle passing 3/4 of the oocyte width. Previous studies have shown that these responses can affect degeneration and fertilisation rates on day 1, however, there is little research on its effect on blastocyst formation rates. Furthermore, most previous studies have used qualitative methods to assess oolemma response. Study design, size, duration This is a retrospective study using ICSI procedure videos conducted by four embryologists in a private clinic from 2013–2015. All videos of procedures which did not result in 2PN or in which the oocyte was not fully visible were excluded. Six operators categorised 455 videos (by majority vote) into four groups based on the oolemma response: oolemma breakage within 1/4, between 1/4 and 1/2, between 1/2 and 3/4 and beyond 3/4 of the oocyte’s width. Participants/materials, setting, methods A U-Net neural network model was trained to extract the frame of maximum oolemma indent from each video which were validated by a human operator; any in which maximum indent occured after breaking of the oolemma were excluded. The ratio of starting to maximal indent width/height were calculated automatically and human-validated. Chi-squared tests were performed for each ratio vs d5/6 blastocyst formation. These results were compared with those obtained from purely human annotations. Main results and the role of chance From the purely human annotations, the percentages of oocytes in groups 1–4 respectively were: 3.3%, 85.3%, 11.4% and 0%. This variation in oolemma response may be due to the arrangement of thick and thin microfilaments or cortical granules in the cytoskeleton. When analysed with d5/6 blastocyst formation, these showed no significant result (p = 0.12) which is consistent with findings using the model. The artificial intelligence (AI) model processed 26 frames per second. During human validation of the ratios calculated at maximal indentation, 36% of width ratios and 31% of height ratios were rejected. The proportion of blastocysts formed in the upper and lower quartile for each ratio was analysed. Both the upper (0.49) and lower (0.41) quartiles of the width ratios were not significant for d5/6 blastocyst formation. The lower (1.12) quartile of height ratios showed no significance, however there were significantly fewer blastocysts formed on d5/6 for the upper (1.18) quartile of height ratios (p < 0.025). This subtle change in the height ratio, which was significant for d5/6 blastocyst formation was not taken into account when grouping oocytes any previous literature (and our human labelling). Limitations, reasons for caution This study was conducted at a single clinic so variations between clinics were not captured in the study and would need further collaborations to confirm the proportion of oocytes responses. Due to the small sample size, this study also did not identify any group 4 oocytes cultured until d5/6. Wider implications of the findings: The grouping criteria in this study were more quantitative than previous work yet indicated no correlation between the oolemma group and d5/6 blastocyst formation. However, changes in the height which are hard to assess in real-time (and which have been neglected in previous literature) were seen to be significant. Trial registration number NA

Differential Effects of Experience and Information Cues on Metacognitive Judgments About Others’ Change Detection Abilities

This study explored the interaction between visual metacognitive judgments about others and cues related to the workings of System 1 and System 2. We examined how intrinsic cues (i.e., saliency of a visual change) and experience cues (i.e., detection/blindness) affect people’s predictions about others’ change detection abilities. In Experiment 1, 60 participants were instructed to notice a subtle and a salient visual change in a magic trick that exploits change blindness, after which they estimated the probability that others would detect the change. In Experiment 2, 80 participants watched either the subtle or the salient version of the trick and they were asked to provide predictions for the experienced change. In Experiment 1, participants predicted that others would detect the salient change more easily than the subtle change, which was consistent with the actual detection reported in Experiment 2. In Experiment 2, participants’ personal experience (i.e., whether they detected the change) biased their predictions. Moreover, there was a significant difference between their predictions and offline predictions from Experiment 1. Interestingly, change blindness led to lower predictions. These findings point to joint contributions of experience and information cues on metacognitive judgments about other people’s change detection abilities.