Crystal Structure of DIM-1, an Acquired Subclass B1 Metallo-β-Lactamase from Pseudomonas stutzeri

Metallo-β-lactamases (MBLs) hydrolyze almost all classes of β-lactam antibiotic, including carbapenems—currently first choice drugs for opportunistic infections by Gram-negative bacterial pathogens. MBL inhibitor development is complicated by the diversity within this group of enzymes, and by the appearance of new enzymes that continue to be identified both as chromosomal genes and on mobile genetic elements. One such newly discovered MBL is DIM-1, a mobile enzyme originally discovered in the opportunist pathogen Pseudomonas stutzeri but subsequently identified in other species and locations. DIM-1 is a subclass B1 MBL more closely related to the TMB-1, GIM-1 and IMP enzymes than to other clinically encountered MBLs such as VIM and NDM; and possesses Arg, rather than the more usual Lys, at position 224 in the putative substrate binding site. Here we report the crystallization and structure determination of DIM-1. DIM-1 possesses a binuclear metal center with a 5 (rather than the more usual 4) co-ordinate tri-histidine (Zn1) site and both 4- and 5-co-ordinate Cys-His-Asp- (Zn2) sites observed in the two molecules of the crystallographic asymmetric unit. These data indicate a degree of variability in metal co-ordination geometry in the DIM-1 active site, as well as facilitating inclusion of DIM-1 in structure-based MBL inhibitor discovery programmes

Semi-stochastic full configuration interaction quantum Monte Carlo: Developments and application.

We expand upon the recent semi-stochastic adaptation to full configuration interaction quantum Monte Carlo (FCIQMC). We present an alternate method for generating the deterministic space without a priori knowledge of the wave function and present stochastic efficiencies for a variety of both molecular and lattice systems. The algorithmic details of an efficient semi-stochastic implementation are presented, with particular consideration given to the effect that the adaptation has on parallel performance in FCIQMC. We further demonstrate the benefit for calculation of reduced density matrices in FCIQMC through replica sampling, where the semi-stochastic adaptation seems to have even larger efficiency gains. We then combine these ideas to produce explicitly correlated corrected FCIQMC energies for the beryllium dimer, for which stochastic errors on the order of wavenumber accuracy are achievable.N.S.B. gratefully acknowledges Trinity College, Cambridge for funding. J.S.S. acknowledges the research environment provided by the Thomas Young Centre under Grant No. TYC-101. G.H.B. gratefully acknowledges the Royal Society for a university research fellowship. This work has been supported by the EPSRC under grant no. EP/J003867/1.This is the author accepted manuscript. The final version is available from AIP at http://scitation.aip.org/content/aip/journal/jcp/142/18/10.1063/1.4920975

Natural selection. II. Developmental variability and evolutionary rate

In classical evolutionary theory, genetic variation provides the source of heritable phenotypic variation on which natural selection acts. Against this classical view, several theories have emphasized that developmental variability and learning enhance nonheritable phenotypic variation, which in turn can accelerate evolutionary response. In this paper, I show how developmental variability alters evolutionary dynamics by smoothing the landscape that relates genotype to fitness. In a fitness landscape with multiple peaks and valleys, developmental variability can smooth the landscape to provide a directly increasing path of fitness to the highest peak. Developmental variability also allows initial survival of a genotype in response to novel or extreme environmental challenge, providing an opportunity for subsequent adaptation. This initial survival advantage arises from the way in which developmental variability smooths and broadens the fitness landscape. Ultimately, the synergism between developmental processes and genetic variation sets evolutionary rate

Reduced orienting to audiovisual synchrony in infancy predicts autism diagnosis at 3 years of age

Background: Effective multisensory processing develops in infancy and is thought to be important for the perception of unified and multimodal objects and events. Previous research suggests impaired multisensory processing in autism, but its role in the early development of the disorder is yet uncertain. Here, using a prospective longitudinal design, we tested whether reduced visual attention to audiovisual synchrony is an infant marker of later-emerging autism diagnosis. Methods: We studied 10-month-old siblings of children with autism using an eye tracking task previously used in studies of preschoolers. The task assessed the effect of manipulations of audiovisual synchrony on viewing patterns while the infants were observing point light displays of biological motion. We analyzed the gaze data recorded in infancy according to diagnostic status at 3 years of age (DSM-5). Results: Ten-month-old infants who later received an autism diagnosis did not orient to audiovisual synchrony expressed within biological motion. In contrast, both infants at low-risk and high-risk siblings without autism at follow-up had a strong preference for this type of information. No group differences were observed in terms of orienting to upright biological motion. Conclusions: This study suggests that reduced orienting to audiovisual synchrony within biological motion is an early sign of autism. The findings support the view that poor multisensory processing could be an important antecedent marker of this neurodevelopmental condition. Keywords: Autism spectrum disorder; infancy; multisensory processing; biological motion; biomarker; scientific replication

Accuracy of self-reported anthropometric measures in older Australian adults

Aim: To determine the accuracy of self-reported anthropometric measurements in older Australian adults 60–70 years. Method: Self-reported anthropometric data from 103 community-dwelling participants (mean age 66 years) were compared with actual measurements. Difference and agreement were assessed using paired t-tests, correlation coefficients and Bland–Altman plots. Results: Underreporting occurred for weight and hip circumference, especially among men, whereas waist circumference was slightly overreported, resulting in apparent underestimations of body mass index (by 0.42 kg/m2) but overestimations of waist-to-hip ratio (WHR, by 0.02). Concordance correlation coefficients were generally high except for WHR. Self-reported circumference measures appeared to be more accurate than the derived WHR. The Bland–Altman plots revealed wide limits of agreement for all measures. Conclusion: Self-reported values correlated well with measured values and average discrepancies were small. However, use of self-reported anthropometric data may be preferable in population studies for describing overall distribution than for monitoring changes at an individual level

The long-term impact of infant rearing background on the affective state of adult common marmosets (Callithrix jacchus)

Early life environment, including temporary family separation, can have a major influence on affective state. Using a battery of tests, the current study compared the performance of adult common marmosets (Callithrix jacchus), reared as infants under 3 different conditions: family-reared twins, family-reared animals from triplet litters where only 2 remain (2stays) and supplementary fed triplets. No significant differences were found in latency to approach and obtain food from a human or a novel object between rearing conditions, suggesting no effect on neophobia. There were no differences in cognitive bias task acquisition time, or proportion of responses to each ambiguous probe. Very minor differences were found in response to the probes, with only supplementary fed marmosets making fewer responses to the middle probe, compared to the probe nearest the rewarded stimuli. Similarly, in a test for anhedonia, no difference was found between rearing conditions in consumption of milkshake at different concentrations. There was just one very small difference in reward motivation, with only supplementary fed triplets demonstrating a lack of preference for milkshake over water at the lowest concentration. This consistent pattern of results suggest that the supplementary feeding of large litters of marmosets at this facility did not have a major effect on welfare, and is unlikely to influence performance in reward-related scientific tasks. Therefore, while family separation is not recommended, this particular practice should be used if it is necessary, such as to reduce infant mortality. Regular positive interactions with humans are also encouraged, to reduce fear and improve welfare of marmosets kept in captivity

Probabilistic models to evaluate effectiveness of steel bridge weld fatigue retrofitting by peening

The purpose of this study was to evaluate, with two probabilistic analytical models, the effectiveness of several alternative fatigue management strategies for steel bridge welds. The investigated strategies employed, in various combinations, magnetic particle inspection, gouging and rewelding, and postweld treatment by peening. The analytical models included a probabilistic strain-based fracture mechanics model and a Markov chain model. For comparing the results obtained with the two models, the fatigue life was divided into a small, fixed number of condition states based on crack depth, similar to those often used by bridge management systems to model deterioration due to other processes, such as corrosion and road surface wear. The probabilistic strain-based fracture mechanics model was verified first by comparison with design S-N curves and test data for untreated welds. Next, the verified model was used to determine the probability that untreated and treated welds would be in each condition state in a given year; the probabilities were then used to calibrate transition probabilities for a much simpler Markov chain fatigue model. Then both models were used to simulate a number of fatigue management strategies. From the results of these simulations, the performance of the different strategies was compared, and the accuracy of the simpler Markov chain fatigue model was evaluated. In general, peening was more effective if preceded by inspection of the weld. The Markov chain fatigue model did a reasonable job of predicting the general trends and relative effectiveness of the different investigated strategies

Food availability outweighs ocean acidification effects in juvenileMytilus edulis: laboratory and field experiments

Ocean acidification is expected to decrease calcification rates of bivalves. Nevertheless in many coastal areas high pCO2 variability is encountered already today. Kiel Fjord (Western Baltic Sea) is a brackish (12-20 g kg-1) and CO2 enriched habitat, but the blue mussel Mytilus edulis dominates the benthic community. In a coupled field and laboratory study we examined the annual pCO2 variability in this habitat and the combined effects of elevated pCO2 and food availability on juvenile M. edulis growth and calcification. In the laboratory experiment, mussel growth and calcification were found to chiefly depend on food supply, with only minor impacts of pCO2 up to 3350 μatm. Kiel Fjord was characterized by strong seasonal pCO2 variability. During summer, maximal pCO2 values of 2500 μatm were observed at the surface and >3000 μatm at the bottom. However, the field growth experiment revealed seven times higher growth and calcification rates of M. edulis at a high pCO2 inner fjord field station (mean pCO2 ca. 1000 μatm) in comparison to a low pCO2 outer fjord station (ca. 600 μatm). In addition, mussels were able to outcompete the barnacle Amphibalanus improvisus at the high pCO2 site. High mussel productivity at the inner fjord site was enabled by higher particulate organic carbon concentrations. Kiel Fjord is highly impacted by eutrophication, which causes bottom water hypoxia and consequently high seawater pCO2. At the same time, elevated nutrient concentrations increase the energy availability for filter feeding organisms such as mussels. Thus M. edulis can dominate over a seemingly more acidification resistant species such as A. improvisus. We conclude that benthic stages of M. edulis tolerate high ambient pCO2 when food supply is abundant and that important habitat characteristics such as species interactions and energy availability need to be considered to predict species vulnerability to ocean acidification

Histopathological indicators: a useful fish health monitoring tool in common carp (Cyprinus carpio Linnaeus, 1758) culture

In order to evaluate the relationship between water quality in ponds and indices of histopathological changes occurring in the vital organs of the common carp (Cyprinus carpio L., 1758), two six-month field experiments were carried out using two different water supplies: from the nearby stream and a tube well. The fish were fed supplemental feed: raw cereals, pelleted and extruded compound feed. Histopathological analysis, alteration frequencies, and semi-quantitative scoring of the changes were used to assess the health status of the fish. Ponds supplied by stream water were characterized by higher water hardness, dissolved oxygen and pH values, while those supplied by the tube well had higher electroconductivity, total ammonium and orthophosphates content. Fish survival rate and habitat suitability index were lower in ponds supplied by stream water, while the weight gain did not differ between the two water supplies. The use of stream water resulted in a higher level of histopathological changes in gills and liver. Among the water quality parameters, pH level had the strongest influence on fish. Differences in water supply produced greater influence on the level of histopathological changes than the type of feed applied. Gills were the most sensitive organ, while the kidney was the least responsive