The transformation of organic amendments (OA) in soil is in large part performed by soil microbial communities. These processes are strongly affected by the carbon composition of the OAs. We examined ...microbial community responses to three types of OA: green waste, composted green waste and pyrolysed green waste added to two contrasting agricultural soils. We investigated the relationship between the soil carbon composition (as determined by 13C-solid state NMR), microbial community composition (as determined by phospholipid fatty acid analysis) and microbial activity (as determined by soil enzyme assays). We found that alkyl-C, O-aryl-C, aryl-C and carbonyl-C were able to explain most of the variations (≥50%) in soil microbial community composition and activity. Aryl-C content (reflecting relatively stable carbon forms) strongly influenced microbial composition, while carbonyl-C content (reflecting relatively labile carbon forms) strongly influenced the microbial activity. Our results confirm that there is a tight relationship between carbon composition and soil microbial community composition and function. Results are discussed in the context of examining the relationship between carbon forms, microbial community composition and activity following the addition of different OAs to the soil.
•Composting and pyrolysis alters carbon forms and stabilises green waste.•Soil C forms explain 57% and 46% variations in microbial composition and activity.•Aryl-C content (∼stable C forms) strongly influenced microbial composition.•Carbonyl-C content (∼labile C forms) strongly influenced microbial activity.•Knowledge of soil C composition improves prediction of organic amendment turnover.
c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive ...Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.
Discovering and optimizing commercially viable materials for clean energy applications typically takes more than a decade. Self-driving laboratories that iteratively design, execute, and learn from ...materials science experiments in a fully autonomous loop present an opportunity to accelerate this research process. We report here a modular robotic platform driven by a model-based optimization algorithm capable of autonomously optimizing the optical and electronic properties of thin-film materials by modifying the film composition and processing conditions. We demonstrate the power of this platform by using it to maximize the hole mobility of organic hole transport materials commonly used in perovskite solar cells and consumer electronics. This demonstration highlights the possibilities of using autonomous laboratories to discover organic and inorganic materials relevant to materials sciences and clean energy technologies.
Osteosarcoma (OS) is the most common cancer of bone and the 5th leading cause of cancer-related death in young adults. Currently, 5-year survival rates have plateaued at ~70% for patients with ...localized disease. Those with disseminated disease have an ~20% 5-year survival. An improved understanding of the molecular genetics of OS may yield new approaches to improve outcomes for OS patients. To this end, we applied murine models that replicate human OS to identify and understand dysregulated microRNAs (miRNAs) in OS. miRNA expression patterns were profiled in murine primary osteoblasts, osteoblast cultures and primary OS cell cultures (from primary and paired metastatic locations) isolated from two genetically engineered murine models of OS. The differentially expressed miRNA were further assessed by a cross-species comparison with human osteoblasts and OS cultures. We identified miR-155-5p and miR-148a-3p as deregulated in OS. miR-155-5p suppression or miR-148a-3p overexpression potently reduced proliferation and induced apoptosis in OS cells, yet strikingly, did not impact normal osteoblasts. To define how these miRNAs regulated OS cell fate, we used an integrated computational approach to identify putative candidate targets and then correlated these with the cell biological impact. Although we could not resolve the mechanism through which miR-148a-3p impacts OS, we identified that miR-155-5p overexpression suppressed its target Ripk1 (receptor (TNFRSF)-interacting serine-threonine kinase 1) expression, and miR-155-5p inhibition elevated Ripk1 levels. Ripk1 is directly involved in apoptosis/necroptosis. In OS cells, small interfering RNA against Ripk1 prevented cell death induced by the sequestration of miR-155-5p. Collectively, we show that miR-148a-3p and miR-155-5p are species-conserved deregulated miRNA in OS. Modulation of these miRNAs was specifically toxic to tumor cells but not normal osteoblasts, raising the possibility that these may be tractable targets for miRNA-based therapies for OS.
Summary
Background/Introduction
Cardio-cerebral infarction (CCI), which involves the simultaneous occurrence of acute ischaemic stroke and acute myocardial infarction, has a reported incidence of ...0.0009%. Treatment of CCI presents a dilemma to physicians as both conditions are time critical. Despite the need for standardized treatment protocols, published data are sparse.
Aim
We aimed to summarize the reported cardio-cerebral infarction cases in the literature.
Design
Meta-analysis.
Methods
Four databases, Pubmed, Embase, Scopus and Google Scholar were searched until 25 August 2020. A title and abstract sieve, full-text review and extraction of data were conducted independently by three authors.
Results
A total of 44 cases of CCI were identified from 37 case reports and series; 15 patients (34.1%) were treated using percutaneous coronary intervention (PCI) with stent, 8 patients (18.2%) were treated with a PCI without stent, 10 patients (22.7%) were treated via a cerebral vessel thrombectomy and 8 patients (18.2%) were treated via a thrombectomy of a coronary vessel. For medications, 20 patients (45.5%) were treated with thrombolytics, 10 patients (22.7%) were treated with anticoagulants, 8 patients (18.2%) were treated with antiplatelets and 11 patients (25.0%) were treated with anticoagulants and antiplatelets. Of 44 patients, 10 patients died, and 9 of those were due to cardiac causes. Among the 44 patients, days to death was observed to be a median of 2.0 days (interquartile range (IQR): 1.5, 4.0). The modified Rankin Score was measured in nine patients, with a median score of 2.0 (IQR: 1.0, 2.5) being reported.
Discussion/Conclusion
The condition of CCI has substantial morbidity and mortality, and further studies are needed to examine the optimal diagnostic and treatment strategies of these patients.
Intrinsic capacity (IC) and frailty are complementary in advancing disability prevention through maintaining functionality.
We examined the relationship between IC and frailty status at baseline and ...1-year, and evaluated if IC decline predicts frailty onset among robust older adults. The secondary objectives investigated associations between IC, physical fitness and health-related outcomes.
Prospective cohort study.
Community-based assessments.
Older adults aged>55 years, who were independent in ambulation (walking aids permitted).
5 domains of IC were assessed at baseline: locomotion (Short Physical Performance Battery, 6-minute walk test), vitality (nutritional status, muscle mass), sensory (self-reported hearing and vision), cognition (self-reported memory, age- and education adjusted cognitive performance), psychological (Geriatric Depression Scale-15, self-reported anxiety/ depression). Composite IC (0-10) was calculated, with higher scores representing greater IC. Frailty status was based on modified Fried criteria, with frailty progression defined as incremental Fried score at 1-year.
809 participants (67.6+6.8 years) had complete data for all 5 IC domains. 489 (60.4%) participants were robust but only 213 (26.3%) had no decline in any IC domain. Pre-frail and frail participants were more likely to exhibit decline in all 5 IC domains (p<0.05), with decremental composite IC 9 (8-9), 8 (6-9), 5.5 (4-7.5), p<0.001 across robust, prefrail and frail. IC was significantly associated with fitness performance, independent of age and gender. Higher composite IC reduced risk for frailty progression (OR=0.62, 95% CI 0.48-0.80), and reduced frailty onset among robust older adults (OR=0.53, 95% CI 0.37-0.77), independent of age, comorbidities and social vulnerability. Participants with higher IC were less likely to experience health deterioration (OR=0.70, 95% CI 0.58-0.83), falls (OR=0.76, 95% CI 0.65-0.90) and functional decline (OR=0.64, 95% CI 0.50-0.83) at 1-year.
Declining IC may present before frailty becomes clinically manifest, increasing risk for poor outcomes. Monitoring of IC domains potentially facilitates personalized interventions to avoid progressive frailty.
The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients ...treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.
Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.
In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35-37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF(V600K/R) versus BRAF(V600E) melanoma in univariate and multivariate analyses.
BRAF and NRAS mutation status does not influence survival in metastatic melanoma.
Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific ...associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors.
We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program.
In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 95% confidence interval (CI) 4.11-20.77 among those aged ≤60 years, 3.00 (95% CI 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI 1.10-1.94) among those aged >70 years (Pheterogeneity = 3×10−5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (Pheterogeneity ≤0.01).
Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.
•We demonstrate an age-dependent pattern of relative risk for nearly all established risk factors for pancreatic cancer.•Associations between risk factors and pancreatic cancer were strongest among younger participants and weakened with age.•The age of target populations should be considered when designing prevention and control programs for pancreatic cancer.
This research evaluated the kinetics of
δ
-phase growth in laser powder bed additively-manufactured (AM) Inconel 625 during post-build stress-relief heat treatments. The temperatures ranged between ...650 °C and 1050 °C, and the times from 0.25 to 168 hours. The presence of
δ
-phase was verified for each temperature/time combination through multiple techniques. A conventional time-temperature-transformation diagram was constructed from the time-temperature data. Comparison to the growth in wrought IN625 with a similar nominal composition revealed that
δ
-phase formation occurred at least two orders of magnitude faster in the AM IN625. The results of this study also revealed that the segregated microstructure in the as-built condition has a strong influence on the kinetics of
δ
-phase formation in AM IN625 as compared to a homogenized material. Since control of the
δ
-phase growth is essential for reliable prediction of the performance of IN625 components in service, avoiding heat treatments that promote the formation of
δ
-phase in AM components that are not homogenized is highly recommended. This will be particularly true at elevated temperatures where the microstructural stability and the consistency of mechanical properties are more likely to be affected by the presence of
δ
-phase.
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