Impact of hot-carrier degradation on the low-frequency noise in MOSFETs under steady-state and periodic large-signal excitation

This letter reports the diagnostic power of the low-frequency noise analysis (steady-state and periodic large-signal excitation) in MOSFETs subjected to hot-carrier degradation. The LF noise under periodic large-signal excitation is shown to increase more rapidly than the LF noise in steady-state. Moreover the improvement in the LF noise performance due to periodic large-signal excitation, observed for fresh devices, gradually diminishes as the devices are subjected to hot-carrier stress

High Production of LukMF' in Staphylococcus aureus Field Strains Is Associated with Clinical Bovine Mastitis

Staphylococcus aureus, a major cause of bovine mastitis, produces a wide range of immune-evasion molecules. The bi-component leukocidin LukMF' is a potent killer of bovine neutrophils in vitro. Since the role of LukMF' in development of bovine mastitis has not been studied in natural infections, we aimed to clarify whether presence of the lukM-lukF' genes and production levels of LukMF' are associated with clinical severity of the disease. Staphylococcus aureus was isolated from mastitis milk samples (38 clinical and 17 subclinical cases) from 33 different farms. The lukM-lukF' genes were present in 96% of the isolates. Remarkably, 22% of the lukM-lukF'-positive S. aureus isolates displayed a 10-fold higher in vitro LukMF' production than the average of the lower-producing ones. These high producing isolates were cultured significantly more frequently from clinical than subclinical mastitis cases. Also, the detection of LukM protein in milk samples was significantly associated with clinical mastitis and high production in vitro. The high producing LukMF' strains all belonged to the same genetic lineage, spa-type t543. Analysis of their global toxin gene regulators revealed a point mutation in the Repressor of toxins (rot) gene which results in a non-functional start codon, preventing translation of rot. This mutation was only identified in high LukMF' producing isolates and not in low LukMF' producing isolates. Since rot suppresses the expression of various toxins including leukocidins, this mutation is a possible explanation for increased LukMF' production. Identification of high LukMF' producing strains is of clinical relevance and can potentially be used as a prognostic marker for severity of mastitis

Predicting self-perceived general health status using machine learning: an external exposome study

BACKGROUND: Self-perceived general health (SPGH) is a general health indicator commonly used in epidemiological research and is associated with a wide range of exposures from different domains. However, most studies on SPGH only investigated a limited set of exposures and did not take the entire external exposome into account. We aimed to develop predictive models for SPGH based on exposome datasets using machine learning techniques and identify the most important predictors of poor SPGH status. METHODS: Random forest (RF) was used on two datasets based on personal characteristics from the 2012 and 2016 editions of the Dutch national health survey, enriched with environmental and neighborhood characteristics. Model performance was determined using the area under the curve (AUC) score. The most important predictors were identified using a variable importance procedure and individual effects of exposures using partial dependence and accumulated local effect plots. The final 2012 dataset contained information on 199,840 individuals and 81 variables, whereas the final 2016 dataset had 244,557 individuals with 91 variables. RESULTS: Our RF models had overall good predictive performance (2012: AUC = 0.864 (CI: 0.852-0.876); 2016: AUC = 0.890 (CI: 0.883-0.896)) and the most important predictors were "Control of own life", "Physical activity", "Loneliness" and "Making ends meet". Subjects who felt insufficiently in control of their own life, scored high on the De Jong-Gierveld loneliness scale or had difficulty in making ends meet were more likely to have poor SPGH status, whereas increased physical activity per week reduced the probability of poor SPGH. We observed associations between some neighborhood and environmental characteristics, but these variables did not contribute to the overall predictive strength of the models. CONCLUSIONS: This study identified that within an external exposome dataset, the most important predictors for SPGH status are related to mental wellbeing, physical exercise, loneliness, and financial status

Genomic analysis of European bovine Staphylococcus aureus from clinical versus subclinical mastitis

Abstract: Intramammary infections (IMI) with Staphylococcus aureus are a common cause of bovine mastitis and can result in both clinical (CM) or subclinical mastitis (SCM). Although bacterial isolates of S. aureus differ in their virulence potential it is largely unclear which bacterial virulence factors are responsible for increased clinical severity. We performed a genome wide association study and used a generalized linear mixed model to investigate the correlation between gene carriage, lineage and clinical outcome of IMI in a collection of S. aureus isolates from cattle with CM (n = 125) and SCM (n = 151) from 11 European countries. An additional aim was to describe the genetic variation of bovine S. aureus in Europa. The dominant lineages in our collection were clonal complex (CC) 151 (81/276, 29.3%), CC97 (54/276, 19.6%), CC479 (32/276, 11.6%) and CC398 (19/276, 6.9%). Virulence and antimicrobial resistance (AMR) gene carriage was highly associated with CC. Among a selection of nine virulence and AMR genes, CC151, CC479 and CC133 carried more virulence genes than other CCs, and CC398 was associated with AMR gene carriage. Whereas CC151, CC97 were widespread in Europe, CC479, CC398 and CC8 were only found in specific countries. Compared to CC151, CC479 was associated with CM rather than SCM (OR 3.62; 95% CI 1.38–9.50) and the other CCs were not. Multiple genes were associated with CM, but due to the clustering within CC of carriage of these genes, it was not possible to differentiate between the effect of gene carriage and CC on clinical outcome of IMI. Nevertheless, this study demonstrates that characterization of S. aureus CC and virulence genes helps to predict the likelihood of the occurrence of CM following S. aureus IMI and highlights the potential benefit of diagnostics tools to identify S. aureus CC during bovine mastitis

Molecular epidemiology and immune evasion strategies of ruminant Staphylococcus aureus

Infections with the Staphylococcus aureus bacteria are a common cause of mastitis in ruminants, causing major financial losses for the dairy industry. The outcome of these infections ranges from mild subclinical cases of mastitis, to severe clinical cases. It is not fully understood if and how the infecting bacteria influences the clinical severity of mastitis. Therefore, this thesis explored the molecular epidemiology and differences in immune evasion strategies of ruminant S. aureus. By comparing the genetic structure of S. aureus responsible for subclinical and clinical cases of bovine mastitis (collected in The Netherlands and 10 other European countries), a specific subtype of S. aureus (belonging to Clonal Complex (CC) 479) was identified that was associated with clinical mastitis. These bacteria produced increased levels of leukocidin LukMF’. This toxin is a potent killer of ruminant immune cells, offering a likely explanation for the increased virulence of CC479 S. aureus. In addition, genetic analysis of all collected isolates demonstrated that only a relatively small number of S. aureus CCs are responsible for bovine mastitis in 11 European countries, with 5 CCs (CC151, CC97, CC479, CC133 and CC398) representing almost 75% of collected bacteria. These ruminant-associated CCs differed greatly in their carriage of virulence genes (e.g. toxin and antibiotic resistance genes) and their distribution between countries. Although multiple virulence genes were associated with clinical mastitis, including several superantigen genes, it was not possible to differentiate between the effect of individual genes and S. aureus CC on clinical severity since carriage of these genes was highly correlated with specific CCs. Similar studies performed using a collection of S. aureus isolates obtained from mastitis cases in goats and sheep, showed no differences in genotype and LukMF’ production between clinical and subclinical isolates. There were, however, small genetic differences between S. aureus collected from goats and goats. Furthermore, we also demonstrated that mammary epithial cells (MEC), key activators of the immune response of the udder during S. aureus infections, respond differently to various ruminant-associated S. aureus CCs. Stimulation with CC133 S. aureus triggered a stronger release of cytokine IL-8 by the bovine MEC line PS than stimulation with CC151, CC479 and CC425 S. aureus. In addition, a preliminary study using primary caprine and bovine primary MEC showed that caprine and bovine MEC had a different cytokine response to stimulation with a cow-associated (CC479) and small ruminant-associated (CC133) strain. The results of this thesis demonstrated that ruminant-associated S. aureus CCs differ in their carriage of immune evasion and antibiotic resistance genes, expression of LukMF’ and their activation of ruminant MEC. Furthermore, CC479 S. aureus were associated with clinical mastitis and this strongly suggests that the type of infecting bacteria influences the clinical severity of mastitis. Knowledge of the genotype of S. aureus responsible for ruminant mastitis could therefore be useful information for veterinarians and farmers to assist them in increasing the effectiveness of mastitis treatment and reduction strategies on dairy farms

Activation of a Bovine Mammary Epithelial Cell Line by Ruminant-Associated Staphylococcus aureus is Lineage Dependent

Bovine mastitis is a costly disease to the dairy industry and intramammary infections (IMI) with Staphylococcus aureus are a major cause of mastitis. Staphylococcus aureus strains responsible for mastitis in cattle predominantly belong to ruminant-associated clonal complexes (CCs). Recognition of pathogens by bovine mammary epithelial cells (bMEC) plays a key role in activation of immune responsiveness during IMI. However, it is still largely unknown to what extent the bMEC response differs according to S. aureus CC. The aim of this study was to determine whether ruminant-associated S. aureus CCs differentially activate bMEC. For this purpose, the immortalized bMEC line PS was stimulated with S. aureus mastitis isolates belonging to four different clonal complexes (CCs; CC133, CC479, CC151 and CC425) and interleukin 8 (IL-8) release was measured as indicator of activation. To validate our bMEC model, we first stimulated PS cells with genetically modified S. aureus strains lacking (protein A, wall teichoic acid (WTA) synthesis) or expressing (capsular polysaccharide (CP) type 5 or type 8) factors expected to affect S. aureus recognition by bMEC. The absence of functional WTA synthesis increased IL-8 release by bMEC in response to bacterial stimulation compared to wildtype. In addition, bMEC released more IL-8 after stimulation with S. aureus expressing CP type 5 compared to CP type 8 or a strain lacking CP expression. Among the S. aureus lineages, isolates belonging to CC133 induced a significantly stronger IL-8 release from bMEC than isolates from the other CCs, and the IL-8 response to CC479 was higher compared to CC151 and CC425. Transcription levels of IL-8, tumor necrosis factor alpha (TNFα), serum amyloid A3 (SAA3), Toll-like receptor (TLR)-2 and nuclear factor κB (NF-κB) in bMEC after bacterial stimulation tended to follow a similar pattern as IL-8 release, but there were no significant differences between the CCs. This study demonstrates a differential activation of bMEC by ruminant-associated CCs of S. aureus, which may have implications for the severity of mastitis during IMI by S. aureus belonging to these lineages

Molecular epidemiology and immune evasion strategies of ruminant Staphylococcus aureus

Infections with the Staphylococcus aureus bacteria are a common cause of mastitis in ruminants, causing major financial losses for the dairy industry. The outcome of these infections ranges from mild subclinical cases of mastitis, to severe clinical cases. It is not fully understood if and how the infecting bacteria influences the clinical severity of mastitis. Therefore, this thesis explored the molecular epidemiology and differences in immune evasion strategies of ruminant S. aureus. By comparing the genetic structure of S. aureus responsible for subclinical and clinical cases of bovine mastitis (collected in The Netherlands and 10 other European countries), a specific subtype of S. aureus (belonging to Clonal Complex (CC) 479) was identified that was associated with clinical mastitis. These bacteria produced increased levels of leukocidin LukMF’. This toxin is a potent killer of ruminant immune cells, offering a likely explanation for the increased virulence of CC479 S. aureus. In addition, genetic analysis of all collected isolates demonstrated that only a relatively small number of S. aureus CCs are responsible for bovine mastitis in 11 European countries, with 5 CCs (CC151, CC97, CC479, CC133 and CC398) representing almost 75% of collected bacteria. These ruminant-associated CCs differed greatly in their carriage of virulence genes (e.g. toxin and antibiotic resistance genes) and their distribution between countries. Although multiple virulence genes were associated with clinical mastitis, including several superantigen genes, it was not possible to differentiate between the effect of individual genes and S. aureus CC on clinical severity since carriage of these genes was highly correlated with specific CCs. Similar studies performed using a collection of S. aureus isolates obtained from mastitis cases in goats and sheep, showed no differences in genotype and LukMF’ production between clinical and subclinical isolates. There were, however, small genetic differences between S. aureus collected from goats and goats. Furthermore, we also demonstrated that mammary epithial cells (MEC), key activators of the immune response of the udder during S. aureus infections, respond differently to various ruminant-associated S. aureus CCs. Stimulation with CC133 S. aureus triggered a stronger release of cytokine IL-8 by the bovine MEC line PS than stimulation with CC151, CC479 and CC425 S. aureus. In addition, a preliminary study using primary caprine and bovine primary MEC showed that caprine and bovine MEC had a different cytokine response to stimulation with a cow-associated (CC479) and small ruminant-associated (CC133) strain. The results of this thesis demonstrated that ruminant-associated S. aureus CCs differ in their carriage of immune evasion and antibiotic resistance genes, expression of LukMF’ and their activation of ruminant MEC. Furthermore, CC479 S. aureus were associated with clinical mastitis and this strongly suggests that the type of infecting bacteria influences the clinical severity of mastitis. Knowledge of the genotype of S. aureus responsible for ruminant mastitis could therefore be useful information for veterinarians and farmers to assist them in increasing the effectiveness of mastitis treatment and reduction strategies on dairy farms

Low-frequency noise in hot-carrier degraded nMOSFETs

This paper discusses the low-frequency (LF) noise in submicron nMOSFETs under controlled transistor aging by hot-carrier stress. Both traditional, steady-state LF noise as well as the LF noise under periodic large-signal excitation were found to increase upon device degradation, for both hydrogen passivated and deuterium passivated Si–SiO2 interfaces. As hot-carrier degradation is slower in deuterium- annealed MOSFETs, so is the increase of the noise in these devices. The noise-suppressing effect of periodic OFF switching is gradually lost during hot-carrier degradation, as the LF noise under periodic large-signal excitation increases more rapidly than the LF noise in steady-state

Differences between Staphylococcus aureus lineages isolated from ovine and caprine mastitis but not between isolates from clinical or subclinical mastitis

Staphylococcus aureus is an important mastitis pathogen, causing both clinical mastitis (CM) and subclinical mastitis (SCM) in small ruminants. In general, CM has a low incidence in sheep and goats but can be very severe and costly. In contrast, subclinical mastitis (SCM) is common but is associated with less cost. For both sheep and goats, S. aureus is the main cause of CM and is associated with SCM cases with a high SCC. Recently, specific lineages of S. aureus have been identified that are associated with CM rather than SCM in dairy cows. It is unknown whether specific S. aureus lineages are associated with CM in goats and sheep. The aim of this study was to compare the clonal complex (CC), staphylococcal protein A (spa) type, leukocidin lukM-lukF' presence, and potential to produce LukMF' in vitro between CM and SCM S. aureus mastitis isolates obtained from sheep and goats. Differences between isolates from different host species were also compared. Ovine (CM, n = 12; SCM, n = 29) and caprine (CM, n = 14; SCM, n = 30) isolates were obtained from 8 sheep flocks and 8 goat herds in the Netherlands. Overall, the isolates belonged to CC133 (85%), CC398 (7%), CC425 (5%), and CC45 (2%). Seventeen spa types were found, including 6 novel types; the predominant types were t2678 (34%), t544 (18%), and t3583 (18%). Although CC133 was dominant among both sheep and goat isolates, spa type CC133/t2678 was associated with ovine isolates, whereas CC133/t544 and CC133/t3583 were found mostly in goats. The presence of lukM-lukF' among the S. aureus isolates was high (87%), especially in CC133 (96%) and CC425 (100%), but the genes were absent in CC45 and CC398. In vitro-cultured lukM-lukF'-positive isolates produced LukM (71 out of 74 positive isolates tested) in the range of 0.4 to 5.0 µg/mL. Interestingly, the goat-associated lineages CC133/t544 and CC133/t3583 produced more LukM in vitro than the sheep-associated CC133/t2678. We found no difference in LukMF' production potential between CM and SCM isolates. In sheep as well as in goats, no association was found between genotype and CM or SCM, demonstrating that the same lineages of S. aureus are responsible for both CM and SCM. These results suggest that subclinically infected animals in a herd or flock likely act as the reservoir of S. aureus causing CM. This highlights the importance of early identification and control of SCM and suggests that controlling SCM within a herd is an effective intervention to prevent CM in small ruminants.http://www.journals.elsevier.com/journal-of-dairy-sciencehj2020Veterinary Tropical Disease