•Mixed kernels function combines the advantages of local and global kernels.•MKF-SVR model is utilized to estimate both pure and impure CO2-oil MMP in CO2-EOR process.•MFK-SVM model is a more ...reliable and stable regression model to predict CO2-oill MMP.•PSO is designed carefully in order to optimize the parameters of mixed kernels function.
Carbon dioxide (CO2) injection into oil reservoirs is considered a mature enhanced oil recovery (EOR) technique for conventional reservoirs. The local displacement efficiency of the CO2-EOR process is highly dependent on the minimum miscibility pressure (MMP), estimating this parameter is critical to design of the CO2 injection process. Traditional empirical methods to test the CO2-oil MMP are time consuming and expensive; derived correlations are fast but not accurate. Therefore, an efficient and reliable method to determine MMP is beneficial. In this study, a mixed kernels function (MKF) based support vector regression (SVR) model was developed and used to predict the MMP for both pure and impure CO2 injection cases. Four parameters were chosen as input parameters: (1) reservoir temperature; (2) average critical temperature; (3) molecular weight of pentane plus (C5+) fraction of crude oil, and; (4) the ratio of volatile components to intermediate components in crude oil. MMP was selected as the desired output parameter to train and test this newly developed model. The performance of basic kernels function based SVR model is compared with that of this newly developed MKF-SVR model. The well-trained MFK-SVR was compared with three well-established published correlations, demonstrated the highest correlation coefficient (R of 0.9381), lowest root mean square error (RMSE of 1.9151), smallest average absolute error (AAE of 1.1406) and maximum absolute error (MAE of 4.6291). We believe that the proposed MFK-SVM model is a more reliable and stable regression model to predict MMP. In addition, a sensitivity analysis was conducted to evaluate the physical correctness. It indicates that the predicted results from the newly developed model are in excellent agreement with previous empirical work.
Most current approaches focused on vulnerability, resilience, and adaptation to climate change frame gender and its influence in a manner out-of-step with contemporary academic and international ...development research. The tendency to rely on analyses of the sexdisaggregated gender categories of 'men' and 'women' as sole or principal divisions explaining the abilities of different people within a group to adapt to climate change, illustrates this problem. This framing of gender persists in spite of established bodies of knowledge that show how roles and responsibilities that influence a persońs ability to deal with climate-induced and other Stressors emerge at the intersection of diverse identity categories, including but not limited to gender, age, seniority, ethnicity, marital status, and livelihoods. Here, we provide a review of relevant literature on this topic and argue that approaching vulnerability to climate change through intersectional understandings of identity can help improve adaptation programming, project design, implementation, and outcomes.
During microbial applications, metabolic burdens can lead to a significant drop in cell performance. Novel synthetic biology tools or multi-step bioprocessing (e.g., fermentation followed by chemical ...conversions) are therefore needed to avoid compromised biochemical productivity from over-burdened cells. A possible solution to address metabolic burden is Division of Labor (DoL) via natural and synthetic microbial consortia. In particular, consolidated bioprocesses and metabolic cooperation for detoxification or cross feeding (e.g., vitamin C fermentation) have shown numerous successes in industrial level applications. However, distributing a metabolic pathway among proper hosts remains an engineering conundrum due to several challenges: complex subpopulation dynamics/interactions with a short time-window for stable production, suboptimal cultivation of microbial communities, proliferation of cheaters or low-producers, intermediate metabolite dilution, transport barriers between species, and breaks in metabolite channeling through biosynthesis pathways. To develop stable consortia, optimization of strain inoculations, nutritional divergence and crossing feeding, evolution of mutualistic growth, cell immobilization, and biosensors may potentially be used to control cell populations. Another opportunity is direct integration of non-bioprocesses (e.g., microbial electrosynthesis) to power cell metabolism and improve carbon efficiency. Additionally, metabolic modeling and
C-metabolic flux analysis of mixed culture metabolism and cross-feeding offers a computational approach to complement experimental research for improved consortia performance.
Emerging data suggest immune checkpoint inhibitors have reduced efficacy in heavily pretreated triple-negative breast cancers (TNBC), but underlying mechanisms are poorly understood. To better ...understand the phenotypic evolution of TNBCs, we studied the genomic and transcriptomic profiles of paired tumors from patients with TNBC.
We collected paired primary and metastatic TNBC specimens from 43 patients and performed targeted exome sequencing and whole-transcriptome sequencing. From these efforts, we ascertained somatic mutation profiles, tumor mutational burden (TMB), TNBC molecular subtypes, and immune-related gene expression patterns. Stromal tumor-infiltrating lymphocytes (stromal TIL), recurrence-free survival, and overall survival were also analyzed.
We observed a typical TNBC mutational landscape with minimal shifts in copy number or TMB over time. However, there were notable TNBC molecular subtype shifts, including increases in the Lehmann/Pietenpol-defined basal-like 1 (BL1, 11.4%-22.6%) and mesenchymal (M, 11.4%-22.6%) phenotypes, and a decrease in the immunomodulatory phenotype (IM, 31.4%-3.2%). The Burstein-defined basal-like immune-activated phenotype was also decreased (BLIA, 42.2%-17.2%). Among downregulated genes from metastases, we saw enrichment of immune-related Kyoto Encyclopedia of Genes and Genomes pathways and gene ontology (GO) terms, and decreased expression of immunomodulatory gene signatures (
< 0.03) and percent stromal TILs (
= 0.03). There was no clear association between stromal TILs and survival.
We observed few mutational shifts, but largely consistent transcriptomic shifts in longitudinally paired TNBCs. Transcriptomic and IHC analyses revealed significantly reduced immune-activating gene expression signatures and TILs in recurrent TNBCs. These data may explain the observed lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to better understand these initial observations.
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The impacts of climate variability and change impinge upon different lives and livelihoods within agrarian populations in complex ways. While academic, donor, and implementer efforts to understand ...and act on this complexity have been profoundly influenced by gender analysis, most contemporary analyses are predicated on a construction of gender as binary (men versus women). This approach runs contrary to current understandings of gender and identity in the wider social science literature, which treats gender as a social categorization that takes meaning from its intersection with other identities, roles, and responsibilities. An emerging adaptation literature takes on this intersectional approach to gender, making conceptual, methodological, and empirical arguments against assessing the vulnerability of agrarian populations to the impacts of climate variability and change through binary gender categories. This literature argues that binary approaches are likely to overlook the specific challenges facing significant portions of any agrarian population, and therefore can result in maladaptive interventions that enhance, instead of ameliorate, the vulnerability of the most marginal and vulnerable. Though this emerging literature makes a compelling case for change, efforts to convince the academic and implementation communities focused on agrarian adaptation to adopt intersectional gender analyses point to two broad research frontiers. First, convincing these communities of the value of this shift will require an expanded, rigorous empirical base of evidence for who is overlooked by binary gender analysis relative to intersectional analysis in particular places. Second, facilitating the implementation of intersectional approaches will require methodological innovations that have thus far been under‐addressed in this literature.
Key points
Brachial artery (BA) shear‐mediated dilatation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk.
Cerebral vascular health is ...often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide.
We show that endothelium‐dependent diameter (dilator) responses are not significantly related between the internal carotid artery (ICA) and BA; nor are endothelium‐independent responses.
Additionally, ICA endothelium‐dependent responses are not related to middle cerebral artery velocity or ICA blood flow reactivity responses to carbon dioxide.
Therefore, assessment of large extracranial cerebral artery vascular health should be quantified via methods specific to the vessel, not via peripheral endothelial function or cerebrovascular reactivity to carbon dioxide.
This study compared internal carotid artery (ICA) and brachial artery (BA) endothelium‐dependent and ‐independent vasodilation. We hypothesized that endothelium‐dependent and ‐independent vasodilation of the ICA and BA would be neither similar in magnitude nor correlated between vessels. In 19 healthy adults (23 ± 6 years, 24 ± 3 kg/m2, six female), endothelium‐dependent dilatation in the ICA was determined via Duplex ultrasound during transiently elevated shear stress caused by increased partial pressure of end‐tidal carbon dioxide using dynamic end‐tidal forcing (+9 mmHg; cerebral flow‐mediated dilatation, cFMD). BA endothelium‐dependent dilatation was assessed via standard flow‐mediated dilatation (FMD). Endothelium‐independent dilatation in the ICA and BA was assessed concurrently for 10 min following administration of 400 µg sublingual glyceryl trinitrate (GTN). Endothelium‐dependent vasodilation of the ICA (3.4 ± 2.4%) was lower than (P = 0.013) and not correlated to that of the BA (7.9 ± 3.3%; r2 = 0.00, P = 0.93). Including baseline diameter and shear‐rate area under the curve as covariates maintained the difference between cFMD and FMD (3.3 ± 4.2% vs. 7.8 ± 3.8%, P = 0.03), while including baseline diameter and baseline shear rate‐adjusted area under the curve as covariates abolished it (5.9 ± 3.7% vs. 5.9.8 ± 3.5%, P = 0.99). GTN‐mediated vasodilation of the ICA (14.3 ± 2.9%) was lower than (P = 0.002) and not correlated to that of the BA (25.5 ± 8.8%; r2 = 0.12, P = 0.19). Adjusting for baseline diameter eliminated the differences in GTN‐induced vasodilation (ICA: 20.1 ± 5.8% vs. BA: 20.4 ± 5.5%; P = 0.93). Differences in endothelium‐dependent responses, and the lack of correlations between arteries, indicates that endothelium‐dependent function cannot be assumed to be related across cerebral and peripheral vasculatures in young, healthy humans.
Key points
Brachial artery (BA) shear‐mediated dilatation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk.
Cerebral vascular health is often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide.
We show that endothelium‐dependent diameter (dilator) responses are not significantly related between the internal carotid artery (ICA) and BA; nor are endothelium‐independent responses.
Additionally, ICA endothelium‐dependent responses are not related to middle cerebral artery velocity or ICA blood flow reactivity responses to carbon dioxide.
Therefore, assessment of large extracranial cerebral artery vascular health should be quantified via methods specific to the vessel, not via peripheral endothelial function or cerebrovascular reactivity to carbon dioxide.
The global threat of antimicrobial resistance has driven the use of high-throughput sequencing techniques to monitor the profile of resistance genes, known as the resistome, in microbial populations. ...The human oral cavity contains a poorly explored reservoir of these genes. Here we analyse and compare the resistome profiles of 788 oral cavities worldwide with paired stool metagenomes. We find country and body site-specific differences in the prevalence of antimicrobial resistance genes, classes and mechanisms in oral and stool samples. Within individuals, the highest abundances of antimicrobial resistance genes are found in the oral cavity, but the oral cavity contains a lower diversity of resistance genes compared to the gut. Additionally, co-occurrence analysis shows contrasting ARG-species associations between saliva and stool samples. Maintenance and persistence of antimicrobial resistance is likely to vary across different body sites. Thus, we highlight the importance of characterising the resistome across body sites to uncover the antimicrobial resistance potential in the human body.
In the 25 years since the hypothesis was first described, therapeutic use of inhibitors of dipeptidyl peptidase‐4 (DPP‐4i) as a novel approach to the treatment of type 2 diabetes has become ...established widely, with several compounds now available to exemplify the class. Although the clinical profiles of members of the DPP‐4i class have been reviewed extensively, the underlying pragmatic small molecular design and pharmaceutical properties of these agents have seldom been addressed in the context of establishment of the class as treatments for type 2 diabetes. Among the reasons contributing to the wide acceptance of DPP‐4i as oral anti‐hyperglycaemic therapy are: (i) the endocrine basis of their pharmacology; (ii) their chemical ‘simplicity’ and low molecular mass; (iii) their pharmacological selectivity for their target mechanism of action; (iv) the nature of physiologically relevant substrates for the enzyme; (v) their relative ease of formulation into tablets; (vi) their efficacy as glucose‐lowering agents; (vii) their absorption, distribution, metabolism and elimination profiles; and (viii) their limited tolerability issues.
What’s new?
This is an intentionally brief review highlighting aspects of the design of dipeptidyl peptidase‐4 (DPP‐4) inhibitors that are often overlooked in more conventional reviews. It has been written primarily with the purpose of informing primary care healthcare professionals.
The review focuses upon how the pharmacology and some properties of small molecules have facilitated the successful development of therapeutic agents.
The review is timely because it is now 25 years since the hypothesis to treat type 2 diabetes with inhibitors of DPP‐4 was first described in the literature.
The chemical and pharmacological properties of DPP‐4 inhibitor drugs that make them suitable for oral therapy of type 2 diabetes are discussed.
Features distinguishing small molecules from biotechnological alternatives are reviewed briefly.
The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of ...Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2–ERIC–PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.
This study presents the application of a cost-effective, unmanned aerial vehicle (UAV) to investigate calving dynamics at a major marine-terminating outlet glacier draining the western sector of the ...Greenland ice sheet. The UAV was flown over Store Glacier on three sorties during summer 2013 and acquired over 2000 overlapping, geotagged images of the calving front at an similar to 40 cm ground sampling distance. Stereo-photogrammetry applied to these images enabled the extraction of high-resolution digital elevation models (DEMs) with vertical accuracies of plus or minus 1.9 m which were used to quantify glaciological processes from early July to late August 2013. The central zone of the calving front advanced by similar to 500 m, whilst the lateral margins remained stable. The orientation of crevasses and the surface velocity field derived from feature tracking indicates that lateral drag is the primary resistive force and that ice flow varies across the calving front from 2.5 m d super(-1) at the margins to in excess of 16 m d super(-1) at the centreline. Ice flux through the calving front is 3.8 107 m3 d super(-1), equivalent to 13.9 Gt a super(-1) and comparable to flux-gate estimates of Store Glacier's annual discharge. Water-filled crevasses were present throughout the observation period but covered a limited area of between 0.025 and 0.24% of the terminus and did not appear to exert any significant control over fracture or calving. We conclude that the use of repeat UAV surveys coupled with the processing techniques outlined in this paper have great potential for elucidating the complex frontal dynamics that characterise large calving outlet glaciers.
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