The Portevin-Le Chatelier (PLC) effect is a phenomenon by which plastic slip in metallic materials becomes unstable, resulting in jerky flow and the onset of inhomogeneous deformation. The PLC effect ...is thought to be fundamentally caused by the dynamic interplay between dislocations and solute atoms. However, this interplay is almost always inaccessible experimentally due to the extremely fine length and time scales over which it occurs. In this paper, simulations of jerky flow in W-O interstitial solid solutions reveal three dynamic regimes emerging from the simulated strain rate-temperature space: one resembling standard solid solution strengthening, another one mimicking solute cloud formation, and a third one where dislocation/solute coevolution leads to jerky flow as a precursor of dynamic strain aging. The simulations are carried out in a stochastic framework that naturally captures rare events in a rigorous manner, providing atomistic resolution over diffusive time scales using no adjustable parameters.
Magnesium is a light metal, with a density two-thirds that of aluminium, is abundant on Earth and is biocompatible; it thus has the potential to improve energy efficiency and system performance in ...aerospace, automobile, defence, mobile electronics and biomedical applications. However, conventional synthesis and processing methods (alloying and thermomechanical processing) have reached certain limits in further improving the properties of magnesium and other metals. Ceramic particles have been introduced into metal matrices to improve the strength of the metals, but unfortunately, ceramic microparticles severely degrade the plasticity and machinability of metals, and nanoparticles, although they have the potential to improve strength while maintaining or even improving the plasticity of metals, are difficult to disperse uniformly in metal matrices. Here we show that a dense uniform dispersion of silicon carbide nanoparticles (14 per cent by volume) in magnesium can be achieved through a nanoparticle self-stabilization mechanism in molten metal. An enhancement of strength, stiffness, plasticity and high-temperature stability is simultaneously achieved, delivering a higher specific yield strength and higher specific modulus than almost all structural metals.
During mechanical deformation of bcc Fe micropillars, a number of different plastic processes is activated, often leading to unstable plastic flow characterized by abrupt plastic discharges. While ...some of these instabilities are scale-free, such as dynamic strain aging (DSA), others such as plastic avalanches are strongly dependent on specimen dimensions, as well as temperature and strain rate. However, while these processes often have completely different underlying physical origins, they are difficult to separate and identify due to their co-occurring nature during plastic deformation. Understanding the onset and the evolution of these plastic mechanisms is thus important to separate their contributions during plastic flow and rationalize their dependence on specimen dimensions. In this work, we perform
in-situ
scanning electron microscopy microcompression tests of Fe micropillars at room-temperature and strain rates between
10
-
4
and
1.0
s
−1
to study their plastic behavior and characterize the resulting deformation microstructures using high-resolution transmission electron microscopy. We develop a numerical model to extract the frequencies inherent to each plastic process and map them to the corresponding physical mechanisms. We find that dislocation avalanches occur on average with a frequency of
3
Hz in the low strain rate range (<
10
-
3
s
−1
) while solute-driven instabilities that result in a negative strain rate sensitivity occur with frequencies around
10
Hz. By contrast, at the highest strains rates (>
10
-
1
s
–1
) the two physical mechanisms become overlap in time with one another with frequencies around
100
Hz. Our frequency analysis agrees well with a DSA behavior controlled by interstitials impurities such as C, N and O and their interaction with dislocations.
Antibiotic treatment of Mycobacterium abscessus disease is toxic and poorly effective and lacks a firm evidence base. Dual β-lactam and β-lactam/β-lactamase inhibitor combinations may be interesting ...leads to improve treatment outcomes.
To summarize the current preclinical studies on dual β-lactam and β-lactam/β-lactamase inhibitor combinations against M. abscessus.
We performed a literature search using the National Center for Biotechnology Information's PubMed interface with additional snowball sampling.
Select combinations of β-lactam antibiotics, as well as β-lactam/β-lactamase inhibitor combinations show promising in vitro activity and synergy against M. abscessus. β-Lactam antibiotics differ in their ability to reach and interfere with their targets and their resistance to the M. abscessus β-lactamase. The synergy is typically observed for combinations of β-lactam antibiotics or a β-lactam antibiotic with a β-lactamase inhibitor. No additional killing capacity was demonstrated in three-drug combinations of synergistic β-lactam antibiotics and a β-lactamase inhibitor. The efficacy of select dual β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations is retained in intracellular infection assays and mouse models, but no combination has a complete preclinical portfolio.
Future clinical strategies should entail either dual β-lactam or β-lactam/β-lactamase inhibitor combinations. Imipenem-ceftaroline and an all-oral tebipenem-avibactam combination are promising leads but still require a complete preclinical portfolio, target product profiles as well as clinical trial confirmation.
Abstract
Background
Microbiome studies report low gut microbial richness and diversity in ulcerative colitis (UC) patients. We explored whether UC patients who reach long-term clinical, endoscopic, ...and histological remission show a gut microbial ecosystem that is similar to healthy individuals.
Methods
We collected 184 stool samples from 111 individuals (UC patients in long remission, short remission, flare, and healthy control subjects). Microbiota was analyzed by amplicon sequencing (16S ribosomal RNA) and quantitative polymerase chain reaction for specific taxa. All UC remission patients were followed-up for 2 years.
Findings
A drop in species diversity and richness, underrepresentation of butyrate producers, and gain of potentially harmful bacteria were significantly detected in samples from disease-flare and short-remission patients. In contrast, Chao1 and Shannon indexes of diversity did not differ among patients in long remission and healthy control subjects. Long-remission patients also presented fecal bacterial composition closer to that in healthy control subjects. There was a positive correlation between Akkermansia muciniphila abundance and time in remission (rs = 0.53, P < .001). Logistic regression analysis showed that a high Shannon index (odds ratio, 4.83; 95% confidence interval, 1.5-20.6) or presence of A. muciniphila (odds ratio, 4.9; 95% confidence interval, 1.12-29.08) in fecal samples at entry was independently associated with clinical remission over a follow-up period of 24 months.
Interpretation
UC patients who achieve long-term remission show evidence of substantial recovery of the gut microbial ecosystem in terms of diversity and composition. Recovery may just reflect adequate control of inflammatory activity, but higher bacterial diversity or the presence of A. muciniphila in fecal samples predicts flare-free outcomes.
Lay Summary
Microbiome studies have shown low gut microbial richness and diversity in ulcerative colitis patients. Patients who achieve long-term remission show evidence of substantial recovery of the gut microbial ecosystem in terms of diversity and composition.
Abstract Background and Aims Intestinal microbiota dysbiosis is implicated in Crohn’s disease CD and may play an important role in triggering postoperative disease recurrence POR. We prospectively ...studied faecal and mucosal microbial recolonisation following ileocaecal resection to identify the predictive value of recurrence-related microbiota. Methods Mucosal and/or faecal samples from 121 CD patients undergoing ileocaecal resection were collected at predefined time points before and after surgery. Ileal biopsies were collected from 39 healthy controls. POR was defined by a Rutgeerts score ≥i2b. The microbiota was evaluated by 16S rRNA sequencing. Prediction analysis was performed using C5.0 and Random Forest algorithms. Results The mucosa-associated microbiota in CD patients was characterised by a depletion of butyrate-producing species (false discovery rate FDR <0.01) and enrichment of Proteobacteria FDR = 0.009 and Akkermansia spp. FDR = 0.02. Following resection, a mucosal enrichment of Lachnospiraceae FDR <0.001 was seen in all patients but in POR patients, also Fusobacteriaceae FDR <0.001 increased compared with baseline. Patients without POR showed a decrease of Streptococcaceae FDR = 0.003 and Actinomycineae FDR = 0.06. The mucosa-associated microbiota profile had good discriminative power to predict POR, and was superior to clinical risk factors. At Month 6, patients experiencing POR had a higher abundance of taxa belonging to Negativicutes FDR = 0.04 and Fusobacteria FDR = 0.04 compared with patients without POR. Conclusions Microbiota recolonisation after ileocaecal resection is different between recurrence and non-recurrence patients, with Fusobacteria as the most prominent player driving early POR. These bacteria involved in the early recolonisation and POR represent a promising therapeutic strategy in the prevention of disease recurrence.
Faecal microbiota transplantation (FMT) is a novel potential therapy for inflammatory bowel diseases, but it is poorly characterised.
We evaluated the performance of the mouse and rat as a ...pre-clinical model for human microbiota engraftment. We then characterised the effect of a single human stool transfer (HST) on a humanised model of DSS-induced colitis. Colonic and faecal microbial communities were analysed using the 16S rRNA approach and clinical manifestations were assessed in a longitudinal setting.
The microbial community of rats showed greater similarity to that of humans, while the microbiome of mice showed less similarity to that of humans. Moreover, rats captured more human microbial species than mice after a single HST. Using the rat model, we showed that HST compensated faecal dysbiosis by restoring alpha-diversity and by increasing the relative abundance of health-related microbial genera. To some extent, HST also modulated the microbial composition of colonic tissue. These faecal and colonic microbial communities alterations led to a relative restoration of colon length, and a significant decrease in both epithelium damage and disease severity. Remarkably, stopping inflammation by removing DSS before HST caused a faster and greater recovery of both microbiome and clinical manifestation features.
Our results indicate that the rat outperforms the mouse as a model for human microbiota engraftment and show that the efficacy of HST can be enhanced when inflammation stimulation is withdrawn. Finally, our findings support a new therapeutic strategy based on the use FMT combined with anti-inflammatory drugs.
The mechanical response of refractory high-entropy alloys (RHEA) can be greatly influenced by local chemical fluctuations. Here, we perform in-situ transmission electron microscopy (TEM) ...nanocompression tests at room temperature of body-centered cubic Nb-Mo-Ta-W RHEA single-crystal nanopillars to understand the reasons behind this at atomic scale. We find that (i) chemical composition is not uniform in space, following certain oscillatory patterns and (ii) that specimen near-surface regions with local ‘soft’ spots favor dislocation nucleation over ‘hard’ ones. Under stress these dislocations glide inwardly, inevitably running into hard local regions adding hardening stresses of up to 400 MPa to the nominal yield stress. These hard local regions act as ‘chemical’ obstacles as revealed by the occurrence of double cross-slip and the formation of prismatic loops. Using electron dispersive spectroscopy along with atomic resolution TEM, we demonstrate that the obstacles correspond to atomic environments presumably rich in W surrounded by misfit edge dislocations.
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Local fluctuations in the chemical composition of high-entropy alloys (HEA) are known to have a significant influence on their mechanical performance. In this work, we conclusively establish a direct ...link between the strength of micron-sized specimens and deviations from equiatomic stoichiometry in body-centered-cubic (bcc) refractory Nb–Mo–Ta–W HEA. We perform a detailed electron dispersive spectroscopy (EDS) line profile analysis of the compressed micropillars after in-situ scanning electron microscopy microcompression tests at room-temperature and strain rates between 10−4 and 10−1 s−1. We find that compositional fluctuations near the micropillar tip is the best quantitative predictor of yield strength over strain rate and grain orientation. In micropillars tip rich in W, we measure a yield strength of 1500 MPa, while for those with a Ta and Nb-rich oscillations, the yield strength is 1000 and 700 MPa, respectively. Finally, our high-resolution TEM analysis reveals the presence of numerous edge dislocations, suggesting that deformation is controlled by nucleation due to the absence of sufficient internal sources.
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•CD more dysbiotic than UC both at the microbial taxonomic and functional level.•E. coli enriched in CD and almost undetected in UC.•Production of propionate driven by E. coli in CD ...and by Anaerostipes hadrus in UC and healthy controls.•Microbial signatures and random forest enabled discrimination of IBD vs. non-IBD and prediction of flare.
Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), affect several million people worldwide. CD and UC are characterized by periods of clinical remission and relapse. Although IBD patients present chronic alterations of the gut microbiome, called dysbiosis, little attention has been devoted to the relapse-related microbiome. To address this gap, we generated shotgun metagenomic data from the stools of two European cohorts—134 Spanish (followed up for one year) and 49 Belgian (followed up for 6 months) subjects—to characterize the microbial taxonomic and metabolic profiles present. To assess the predictive value of microbiome data, we added the taxonomic profiles generated from a previous study of 130 Americans. Our results revealed that CD was more dysbiotic than UC compared to healthy controls (HC) and that strategies for energy extraction and propionate production were different in CD compared to UC and HC. Remarkably, CD and UC relapses were not associated with alpha- or beta-diversity, or with a dysbiotic score. However, CD relapse was linked to alterations at the species and metabolic pathway levels, including those involved in propionate production. The random forest method using taxonomic profiles allowed the prediction of CD vs. non-CD with an AUC = 0.938, UC vs. HC with an AUC = 0.646, and CD relapse vs. remission with an AUC = 0.769. Our study validates previous taxonomic findings, points to different relapse-related growth and defence mechanisms in CD compared to UC and HC and provides biomarkers to discriminate IBD subtypes and predict disease activity.
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