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Advanced Geothermal Systems (AGS) may in principle be able to satisfy the global energy demand using standard continental-crust geothermal temperature gradients of 25–35 ∘ C/km. However, conventional mechanical rotary drilling is still too expensive to cost-competitively provide the required borehole depths and lengths for AGS. This highlights the need for a new, cheaper drilling technology, such as Plasma-Pulse Geo-Drilling (PPGD), to improve the economic feasibility of AGS. PPGD is a rather new drilling method and is based on nanoseconds-long, high-voltage pulses to fracture the rock without mechanical abrasion. The absence of mechanical abrasion prolongs the bit lifetime, thereby increasing the penetration rate. Laboratory experiments under ambient-air conditions and comparative analyses (which assume drilling at a depth between 3.5 and 4.5 km) have shown that PPGD may reduce drilling costs by approximately 17–23%, compared to the costs of mechanical drilling, while further research and development are expected to reduce PPGD costs further. However, the performance of the PPGD process under deep wellbore conditions, i.e., at elevated temperatures as well as elevated lithostatic and hydrostatic pressures, has yet to be systematically tested. In this paper, we introduce a standard experiment parameter to examine the impact of deep wellbore conditions on PPGD performance, namely the productivity (the excavated rock volume per pulse) and the specific energy (the amount of energy required to drill a unit volume of rock). We employ these parameters to investigate the effect of temperature on PPGD performance, with temperatures increasing up to 80 ∘ C, corresponding to a drilling depth of up to approximately 3 km. Highlights: This study introduces an experiment protocol for studying the impact of deep wellbore conditions on Plasma-Pulse Geo-Drilling performance. When deionized water is used, increasing the temperature decreases Plasma-Pulse Geo-Drilling productivity and increases the specific energy. The effect of increasing temperature on Plasma-Pulse Geo-Drilling depends significantly on the drilling fluid used. Deionized water negatively affects Plasma-Pulse Geo-Drilling, while other studies have shown that the effect of oil-based drilling muds is negligible. [ABSTRACT FROM AUTHOR]

Homograft heart valves may have significant advantages and are preferred for the repair of congenital valve malformations, especially in young women of childbearing age, athletes and in patients with active endocarditis. A growing problem, however, is the mismatch between tissue donation and the increasing demand. The aim of this paper is to describe the initiation process of a homograft procurement program to attenuate the shortage of organs. A comprehensive description of the infrastructure and procedural steps required to initiate a cardiac and vascular tissue donation program combined with a prospective follow-up of all homografts explanted at our institution. Between January 2020 and May 2022, 28 hearts and 12 pulmonary bifurcations were harvested at our institution and delivered to the European homograft bank. Twenty-seven valves (19 pulmonary valves, 8 aortic valves) were processed and allocated for implantation. The reasons for discarding a graft were either contamination (n = 14), or morphology (n = 13) or leaflet damage (n = 2). Five homografts (3 PV, 2 AV) have been cryopreserved and stored while awaiting allocation. One pulmonary homograft with a leaflet cut was retrieved by bicuspidization technique and awaits allocation, as a highly requested small diameter graft. The implementation of a tissue donation program in cooperation with a homograft bank can be achieved with reasonable additional efforts at a transplant center with an in-house cardiac surgery department. Challenging situations with a potential risk of tissue injury during procurement include re-operation, harvesting by a non-specialist surgeon and prior central cannulation for mechanical circulatory support. [ABSTRACT FROM AUTHOR]

Purpose: PREF-NET reported patients’ experience of Somatuline® (lanreotide) Autogel® (LAN) administration at home and in hospital among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Methods: PREF-NET was a multicentre, cross-sectional study of UK adults (aged ≥ 18 years) with GEP-NETs receiving a stable dose of LAN, which comprised of (1) a quantitative online survey, and (2) qualitative semi-structured interviews conducted with a subgroup of survey respondents. The primary objective was the description of overall patient preference for home versus hospital administration of LAN. Secondary objectives included describing patient-reported opinions on the experience and associated preference for each administration setting, and the impact on healthcare utilisation, societal cost, activities of daily living and health-related quality of life (HRQoL). Results: In the primary analysis (80 patients; mean age 63.9 years), 98.7% (95% confidence interval [CI]: 96.1–100.0) of patients preferred to receive LAN at home, compared with 1.3% (95% CI: 0.0–3.9) who preferred the hospital setting. Among participants, over half (60.3%) received their injection from a non-healthcare professional. Most patients (79.5% [95% CI: 70.5–88.4]) reported a positive effect on HRQoL after the switch from hospital to home administration. Qualitative interviews (20 patients; mean age 63.6 years) highlighted that patients preferred home administration because it improved overall convenience; saved time and costs; made them feel more comfortable and relaxed, and less stressed; and increased confidence in their ability to self-manage their treatment. Conclusion: Almost all patients preferred to receive LAN treatment at home rather than in hospital with increased convenience and psychological benefits reported as key reasons for this preference. [ABSTRACT FROM AUTHOR]

Terahertz time-domain spectroscopy (THz-TDS) can be used to map spatial variations in electrical properties such as sheet conductivity, carrier density, and carrier mobility in graphene. Here, we consider wafer-scale graphene grown on germanium by chemical vapor deposition with non-uniformities and small domains due to reconstructions of the substrate during growth. The THz conductivity spectrum matches the predictions of the phenomenological Drude–Smith model for conductors with non-isotropic scattering caused by backscattering from boundaries and line defects. We compare the charge carrier mean free path determined by THz-TDS with the average defect distance assessed by Raman spectroscopy, and the grain boundary dimensions as determined by transmission electron microscopy. The results indicate that even small angle orientation variations below 5° within graphene grains influence the scattering behavior, consistent with significant backscattering contributions from grain boundaries. [ABSTRACT FROM AUTHOR]

Key message: We demonstrate potential for improved multi-environment genomic prediction accuracy using structural variant markers. However, the degree of observed improvement is highly dependent on the genetic architecture of the trait. Breeders commonly use genetic markers to predict the performance of untested individuals as a way to improve the efficiency of breeding programs. These genomic prediction models have almost exclusively used single nucleotide polymorphisms (SNPs) as their source of genetic information, even though other types of markers exist, such as structural variants (SVs). Given that SVs are associated with environmental adaptation and not all of them are in linkage disequilibrium to SNPs, SVs have the potential to bring additional information to multi-environment prediction models that are not captured by SNPs alone. Here, we evaluated different marker types (SNPs and/or SVs) on prediction accuracy across a range of genetic architectures for simulated traits across multiple environments. Our results show that SVs can improve prediction accuracy, but it is highly dependent on the genetic architecture of the trait and the relative gain in accuracy is minimal. When SVs are the only causative variant type, 70% of the time SV predictors outperform SNP predictors. However, the improvement in accuracy in these instances is only 1.5% on average. Further simulations with predictors in varying degrees of LD with causative variants of different types (e.g., SNPs, SVs, SNPs and SVs) showed that prediction accuracy increased as linkage disequilibrium between causative variants and predictors increased regardless of the marker type. This study demonstrates that knowing the genetic architecture of a trait in deciding what markers to use in large-scale genomic prediction modeling in a breeding program is more important than what types of markers to use. [ABSTRACT FROM AUTHOR]

To analyse the strength and mechanical behaviour of hip implants, it is essential to employ an appropriate loading model. Generating computational models supplemented with muscle forces is a complicated task, especially in the initial phase of implant development. This research aims to expand the possibilities of the simpler acetabular cage model based on joint loads without significantly increasing the demand for computing resources. A Python script covered and grouped the loads from daily activities. The ten calculated major loads were compared with the maximum of the walking and stair climbing loads through the finite element analyses of a custom-made acetabular cage. Sensitivity analyses were performed for the surrounding bones' elastic modulus and the pelvis boundary conditions. The major loads can geometrically cover the entire load spectrum of daily activities. The effect of many high-magnitude force vectors is uncertain in the approach that uses the most common maximum loads. Using these resultant major loads, a new stress concentration area could be detected on the acetabular cage, besides the stress concentration areas induced by the loads reported in the literature. The qualitative correctness of the results is also supported by a control computed tomography scan: a fracture occurred in an extensive, high-stress zone. The results are not sensitive to changes in the elastic modulus of the surrounding bone and the boundary conditions of the model. The presented load vectors and the algorithm make more extensive static analyses possible with little computational overhead. The proposed method can be used for checking the static strength of similar implants. [ABSTRACT FROM AUTHOR]

Eye movement perimetry (EMP) is a paradigm developed to assess the visual field without the necessity of suppressing the natural eye movements during the test. Unlike the standard automated perimetry (SAP) where the patient's responses are recorded using a button, EMP uses the natural eye movements reflex as responses during the evaluation. The reliability of EMP depends on correctly determining whether a stimulus is seen or not which, in turn, depends on an adequate analysis of the eye movement data. However, many studies in EMP have focused on characterizing eye movements and only a few authors have documented their methods to determine whether a peripheral stimulus was seen during the test. Furthermore, many of them use static thresholds to perform the classification, but it is not clear how these threshold values were obtained. Based on the foregoing, we develop a threshold test based on FASTPAC C24-2 and EMP for the visual field assessment. Our method uses two machine learning techniques: (1) cascaded K-Means and Bayesian classifiers (KBC) and (2) an Artificial Neural Network (ANN) to classify whether a stimulus was seen or not. Our method was validated with twenty healthy participants (13 women and 7 men) aged 19–43 years (µ = 26 ± 5 years), where the participants performed both an EMP test and an SAP emulation test. Results were compared with gaze trajectories annotations performed by an expert, obtaining accuracy values between 96.8% and 98.9% for KBC and ANN, and values between 90.5% and 92% for SAP emulation. [ABSTRACT FROM AUTHOR]

Myeloid cells form an essential component of initial responses to environmental hazards and toxic exposures. The ability to model these responses in vitro is central to efforts tasked with identifying hazardous materials and understanding mechanisms of injury and disease. Induced pluripotent stem cell (iPSC) derived cells have been suggested as alternatives to more established primary cell testing systems for these purposes. iPSC derived macrophage and dendritic like cells were compared to CD34+ haematopoietic stem cell derived populations using transcriptomic analysis. Using single cell sequencing-based characterisation of iPSC derived myeloid cells, we identified transitional, mature and M2 like macrophages as well as dendritic like antigen presenting cells and fibrocytes. Direct transcriptomic comparisons between iPSC and CD34+ cell derived populations revealed higher expression of myeloid differentiation genes such as MNDA, CSF1R and CSF2RB in CD34+ cells, while iPSC populations had higher fibroblastic and proliferative markers. Exposure of differentiated macrophage populations to nanoparticle alone or in combination with dust mite, resulted in differential gene expression on combination only, with responses markedly absent in iPSC compared to CD34+ derived cells. The lack of responsiveness in iPSC derived cells may be attributable to lower levels of dust mite component receptors CD14, TLR4, CLEC7A and CD36. In summary, iPSC derived myeloid cells display typical characteristics of immune cells but may lack a fully mature phenotype to adequately respond to environmental exposures. [ABSTRACT FROM AUTHOR]

Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases. [ABSTRACT FROM AUTHOR]

The airway epithelium represents the main barrier between inhaled air and the tissues of the respiratory tract and is therefore an important point of contact with xenobiotic substances into the human body. Several studies have recently shown that in vitro models of the airway grown at an air–liquid interface (ALI) can be particularly useful to obtain mechanistic information about the toxicity of chemical compounds. However, such methods are not very amenable to high throughput since the primary cells cannot be expanded indefinitely in culture to obtain a sustainable number of cells. Induced pluripotent stem cells (iPSCs) have become a popular option in the recent years for modelling the airways of the lung, but despite progress in the field, such models have so far not been assessed for their ability to metabolise xenobiotic compounds and how they compare to the primary bronchial airway model (pBAE). Here, we report a comparative analysis by TempoSeq (oligo-directed sequencing) of an iPSC-derived airway model (iBAE) with a primary bronchial airway model (pBAE). The iBAE and pBAE were differentiated at an ALI and then evaluated in a 5-compound screen with exposure to a sub-lethal concentration of each compound for 24 h. We found that despite lower expression of xenobiotic metabolism genes, the iBAE similarly predicted the toxic pathways when compared to the pBAE model. Our results show that iPSC airway models at ALI show promise for inhalation toxicity assessments with further development. [ABSTRACT FROM AUTHOR]

It is well-known that the presence of geometry heterogeneity in porous media enhances solute mass mixing due to fluid velocity heterogeneity. However, laboratory measurements are still sparse on characterization of the role of high-permeability inclusions on solute transport, in particularly concerning fractured porous media. In this study, the transport of solutes is quantified after a pulse-like injection of soluble fluorescent dye into a 3D-printed fractured porous medium with distinct high-permeability (H-k) inclusions. The solute concentration and the pore-scale fluid velocity are determined using laser-induced fluorescence and particle image velocimetry techniques. The migration of solute is delineated with its breakthrough curve (BC), temporal and spatial moments, and mixing metrics (including the scalar dissipation rate, the volumetric dilution index, and the flux-related dilution index) in different regions of the medium. With the same H-k inclusions, compared to a H-k matrix, the low-permeability (L-k) matrix displays a higher peak in its BC, less solute mass retention, a higher peak solute velocity, a smaller peak dispersion coefficient, a lower mixing rate, and a smaller pore volume being occupied by the solute. The flux-related dilution index clearly captures the striated solute plume tails following the streamlines along dead-end fractures and along the interface between the H-k and L-k matrices. We propose a normalization of the scalar dissipation rate and the volumetric dilution index with respect to the maximum regional total solute mass, which offers a generalized examination of solute mixing for an open region with a varying total solute mass. Our study presents insights into the interplay between the geometric features of the fractured porous medium and the solute transport behaviors at the pore scale. [ABSTRACT FROM AUTHOR]

We study the problem of deconvolution for light-sheet microscopy, where the data is corrupted by spatially varying blur and a combination of Poisson and Gaussian noise. The spatial variation of the point spread function of a light-sheet microscope is determined by the interaction between the excitation sheet and the detection objective PSF. We introduce a model of the image formation process that incorporates this interaction and we formulate a variational model that accounts for the combination of Poisson and Gaussian noise through a data fidelity term consisting of the infimal convolution of the single noise fidelities, first introduced in L. Calatroni et al. (SIAM J Imaging Sci 10(3):1196–1233, 2017). We establish convergence rates and a discrepancy principle for the infimal convolution fidelity and the inverse problem is solved by applying the primal–dual hybrid gradient (PDHG) algorithm in a novel way. Numerical experiments performed on simulated and real data show superior reconstruction results in comparison with other methods. [ABSTRACT FROM AUTHOR]

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32–87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9–130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54–13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56–29.5) (p < 0.05) in the multivariate analysis. Lesions 11–20 mm in size had OR 11.1 (1.16–106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81–0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed. [ABSTRACT FROM AUTHOR]

Historically, the central mesencephalic reticular formation has been regarded as a purely horizontal gaze center based on the fact that electrical stimulation of this region produces horizontal saccades, it provides monosynaptic input to medial rectus motoneurons, and cells recorded in this region often display a peak in firing when horizontal saccades are made. We tested the proposition that the central mesencephalic reticular formation is purely a horizontal gaze center by examining whether this region also supplies terminals to superior rectus and levator palpebrae superioris motoneurons, both of which fire when making vertical eye movements. The experiments were carried out using dual tracer techniques at the light and electron microscopic level in macaque monkeys. Injections of biotinylated dextran amine or Phaseolus vulgaris leukoagglutinin into the central mesencephalic reticular formation produced anterogradely labeled terminals that were in synaptic contact with superior rectus and levator palpebrae superioris motoneurons that had been retrogradely labeled. These results indicate that this region is not purely connected with horizontal gaze motoneurons. In addition, we found that the number of contacts on vertical gaze motoneurons increased with more rostral injections involving the mesencephalic reticular formation adjacent to the interstitial nucleus of Cajal. This suggests that there is a caudal to rostral gradient for horizontal to vertical saccades, respectively, represented within the midbrain reticular formation. Finally, we utilized post-embedding immunohistochemistry to show that a portion of the labeled terminals were GABAergic, indicating they likely originate from downgaze premotor neurons. [ABSTRACT FROM AUTHOR]

Due to spatial scaling effects, there is a discrepancy in mineral dissolution rates measured at different spatial scales. Many reasons for this spatial scaling effect can be given. We investigate one such reason, i.e., how pore-scale spatial heterogeneity in porous media affects overall mineral dissolution rates. Using the bundle-of-tubes model as an analogy for porous media, we show that the Darcy-scale reaction order increases as the statistical similarity between the pore sizes and the effective-surface-area ratio of the porous sample decreases. The analytical results quantify mineral spatial heterogeneity using the Darcy-scale reaction order and give a mechanistic explanation to the usage of reaction order in Darcy-scale modeling. The relation is used as a constitutive relation of reactive transport at the Darcy scale. We test the constitutive relation by simulating flow-through experiments. The proposed constitutive relation is able to model the solute breakthrough curve of the simulations. Our results imply that we can infer mineral spatial heterogeneity of a porous media using measured solute concentration over time in a flow-through dissolution experiment. [ABSTRACT FROM AUTHOR]

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder caused by a point mutation in the LMNA gene (LMNA c.1824 C > T), resulting in the production of a detrimental protein called progerin. Adenine base editors recently emerged with a promising potential for HGPS gene therapy. However adeno-associated viral vector systems currently used in gene editing raise concerns, and the long-term effects of heterogeneous mutation correction in highly proliferative tissues like the skin are unknown. Here we use a non-integrative transient lentiviral vector system, expressing an adenine base editor to correct the HGPS mutation in the skin of HGPS mice. Transient adenine base editor expression corrected the mutation in 20.8-24.1% of the skin cells. Four weeks post delivery, the HGPS skin phenotype was improved and clusters of progerin-negative keratinocytes were detected, indicating that the mutation was corrected in both progenitor and differentiated skin cells. These results demonstrate that transient non-integrative viral vector mediated adenine base editor expression is a plausible approach for future gene-editing therapies. Base editing to treat diseases is progressing but tissue delivery and progenitor cells correction are challenging. Here, the authors show sustained effects and propagation of mutation-corrected progenitors by transient adenine base editor expression, improving the skin phenotype of HGPS mice. [ABSTRACT FROM AUTHOR]

The pleiotropic function of long noncoding RNAs is well recognized, but their direct role in governing metabolic homeostasis is less understood. Here, we describe a human adipocyte-specific lncRNA, ADIPINT, that regulates pyruvate carboxylase, a pivotal enzyme in energy metabolism. We developed an approach, Targeted RNA-protein identification using Orthogonal Organic Phase Separation, which identifies that ADIPINT binds to pyruvate carboxylase and validated the interaction with electron microscopy. ADIPINT knockdown alters the interactome and decreases the abundance and enzymatic activity of pyruvate carboxylase in the mitochondria. Reduced ADIPINT or pyruvate carboxylase expression lowers adipocyte lipid synthesis, breakdown, and lipid content. In human white adipose tissue, ADIPINT expression is increased in obesity and linked to fat cell size, adipose insulin resistance, and pyruvate carboxylase activity. Thus, we identify ADIPINT as a regulator of lipid metabolism in human white adipocytes, which at least in part is mediated through its interaction with pyruvate carboxylase. Adipocyte-expressed long non-coding RNAs (lncRNAs) have been shown to regulate the transcription of genes involved in lipid metabolism. Here the authors describe a human adipocyte-specific lncRNA, ADIPINT, which regulates lipid metabolism in white adipocytes in part through its interaction with the metabolic enzyme pyruvate carboxylase. [ABSTRACT FROM AUTHOR]

Background and Aims: Nitrogenous fertilizers provide a short-lived benefit to crops in agroecosystems, but stimulate nitrification and denitrification, processes that result in nitrate pollution, N2O production, and reduced soil fertility. Recent advances in plant microbiome science suggest that genetic variation in plants can modulate the composition and activity of rhizosphere N-cycling microorganisms. Here we attempted to determine whether genetic variation exists in Zea mays for the ability to influence the rhizosphere nitrifier and denitrifier microbiome under “real-world” conventional agricultural conditions.To capture an extensive amount of genetic diversity within maize we grew and sampled the rhizosphere microbiome of a diversity panel of germplasm that included ex-PVP inbreds (Z. mays ssp. mays), ex-PVP hybrids (Z. mays ssp. mays), and teosinte (Z. mays ssp. mexicana and Z. mays ssp. parviglumis). From these samples, we characterized the microbiome, a suite of microbial genes involved in nitrification and denitrification and carried out N-cycling potential assays.Here we are showing that populations/genotypes of a single species can vary in their ecological interaction with denitrifers and nitrifers. Some hybrid and teosinte genotypes supported microbial communities with lower potential nitrification and potential denitrification activity in the rhizosphere, while inbred genotypes stimulated/did not inhibit these N-cycling activities. These potential differences translated to functional differences in N2O fluxes, with teosinte plots producing less GHG than maize plots.Taken together, these results suggest that Zea genetic variation can lead to changes in N-cycling processes that result in N leaching and N2O production, and thereby are selectable targets for crop improvement. Understanding the underlying genetic variation contributing to belowground microbiome N-cycling into our conventional agricultural system could be useful for sustainability.Methods: Nitrogenous fertilizers provide a short-lived benefit to crops in agroecosystems, but stimulate nitrification and denitrification, processes that result in nitrate pollution, N2O production, and reduced soil fertility. Recent advances in plant microbiome science suggest that genetic variation in plants can modulate the composition and activity of rhizosphere N-cycling microorganisms. Here we attempted to determine whether genetic variation exists in Zea mays for the ability to influence the rhizosphere nitrifier and denitrifier microbiome under “real-world” conventional agricultural conditions.To capture an extensive amount of genetic diversity within maize we grew and sampled the rhizosphere microbiome of a diversity panel of germplasm that included ex-PVP inbreds (Z. mays ssp. mays), ex-PVP hybrids (Z. mays ssp. mays), and teosinte (Z. mays ssp. mexicana and Z. mays ssp. parviglumis). From these samples, we characterized the microbiome, a suite of microbial genes involved in nitrification and denitrification and carried out N-cycling potential assays.Here we are showing that populations/genotypes of a single species can vary in their ecological interaction with denitrifers and nitrifers. Some hybrid and teosinte genotypes supported microbial communities with lower potential nitrification and potential denitrification activity in the rhizosphere, while inbred genotypes stimulated/did not inhibit these N-cycling activities. These potential differences translated to functional differences in N2O fluxes, with teosinte plots producing less GHG than maize plots.Taken together, these results suggest that Zea genetic variation can lead to changes in N-cycling processes that result in N leaching and N2O production, and thereby are selectable targets for crop improvement. Understanding the underlying genetic variation contributing to belowground microbiome N-cycling into our conventional agricultural system could be useful for sustainability.Results: Nitrogenous fertilizers provide a short-lived benefit to crops in agroecosystems, but stimulate nitrification and denitrification, processes that result in nitrate pollution, N2O production, and reduced soil fertility. Recent advances in plant microbiome science suggest that genetic variation in plants can modulate the composition and activity of rhizosphere N-cycling microorganisms. Here we attempted to determine whether genetic variation exists in Zea mays for the ability to influence the rhizosphere nitrifier and denitrifier microbiome under “real-world” conventional agricultural conditions.To capture an extensive amount of genetic diversity within maize we grew and sampled the rhizosphere microbiome of a diversity panel of germplasm that included ex-PVP inbreds (Z. mays ssp. mays), ex-PVP hybrids (Z. mays ssp. mays), and teosinte (Z. mays ssp. mexicana and Z. mays ssp. parviglumis). From these samples, we characterized the microbiome, a suite of microbial genes involved in nitrification and denitrification and carried out N-cycling potential assays.Here we are showing that populations/genotypes of a single species can vary in their ecological interaction with denitrifers and nitrifers. Some hybrid and teosinte genotypes supported microbial communities with lower potential nitrification and potential denitrification activity in the rhizosphere, while inbred genotypes stimulated/did not inhibit these N-cycling activities. These potential differences translated to functional differences in N2O fluxes, with teosinte plots producing less GHG than maize plots.Taken together, these results suggest that Zea genetic variation can lead to changes in N-cycling processes that result in N leaching and N2O production, and thereby are selectable targets for crop improvement. Understanding the underlying genetic variation contributing to belowground microbiome N-cycling into our conventional agricultural system could be useful for sustainability.Conclusion: Nitrogenous fertilizers provide a short-lived benefit to crops in agroecosystems, but stimulate nitrification and denitrification, processes that result in nitrate pollution, N2O production, and reduced soil fertility. Recent advances in plant microbiome science suggest that genetic variation in plants can modulate the composition and activity of rhizosphere N-cycling microorganisms. Here we attempted to determine whether genetic variation exists in Zea mays for the ability to influence the rhizosphere nitrifier and denitrifier microbiome under “real-world” conventional agricultural conditions.To capture an extensive amount of genetic diversity within maize we grew and sampled the rhizosphere microbiome of a diversity panel of germplasm that included ex-PVP inbreds (Z. mays ssp. mays), ex-PVP hybrids (Z. mays ssp. mays), and teosinte (Z. mays ssp. mexicana and Z. mays ssp. parviglumis). From these samples, we characterized the microbiome, a suite of microbial genes involved in nitrification and denitrification and carried out N-cycling potential assays.Here we are showing that populations/genotypes of a single species can vary in their ecological interaction with denitrifers and nitrifers. Some hybrid and teosinte genotypes supported microbial communities with lower potential nitrification and potential denitrification activity in the rhizosphere, while inbred genotypes stimulated/did not inhibit these N-cycling activities. These potential differences translated to functional differences in N2O fluxes, with teosinte plots producing less GHG than maize plots.Taken together, these results suggest that Zea genetic variation can lead to changes in N-cycling processes that result in N leaching and N2O production, and thereby are selectable targets for crop improvement. Understanding the underlying genetic variation contributing to belowground microbiome N-cycling into our conventional agricultural system could be useful for sustainability. [ABSTRACT FROM AUTHOR]

We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis. [ABSTRACT FROM AUTHOR]

Schiff bases are organic compounds referred as privileged ligands that are synthesized from the condensation of a primary amine with a carbonyl group. They are regarded as an important class of organic compounds due to their chelating properties and ability to coordinate to a wide range of transition, lanthanide, and actinide ions in different oxidation states using their nitrogen and oxygen atoms to form stable complexes. Tremendous interest has been aroused to explore the potential applications of metal complexes of various Schiff bases in confronting the challenges facing mankind such as antimicrobial resistance and environmental pollution. There has been great interest in Schiff bases and their metal complexes because of their numerous applications in organic, bioinorganic, analytical, material science, and medicinal chemistry. The presence of the azomethine group in the Schiff bases and its ability to coordinate to various metal ions is essential for these applications. This paper covers a wide range of Schiff bases synthesized from the condensation reaction involving the carbonyl group of salicylidene-4-amioantipyrine and the amine group of various organic compounds and their metal complexes which were characterized based on their numerous unique physical, chemical, and spectral properties from which different structures have been proposed. The various information was collected from researches in journals indexed by Scopus, Google Scholar, PubMed published over the years. This review provides an insight into the metal complexes of Schiff bases derived from salicylidene-4-aminoatipyrine and its derivatives and the various research works explored on its biological and analytical applications. [ABSTRACT FROM AUTHOR]

Aims: As the first long-term RCT on insoluble cereal fibre, the optimal fibre trial demonstrated glycometabolic benefits, confirming cohort studies. The combined study intervention of lifestyle recommendations and supplementation with insoluble oat hulls fibre allows to clarify, which amount of fibre is required for a beneficial effect. Methods: One hundred and eighty participants with impaired glucose tolerance underwent the one-year PREDIAS lifestyle programme and received a blinded, randomized fibre or placebo supplement for two years. We conducted a regression analyses and cut-off-based tertile comparisons in subjects with full data on dietary compliance (food records and accounted supplement; n = 120) after one year, investigating effects on fasting blood parameters, oral glucose tolerance test and anthropometry. Results: We found a nonlinear inverse relation between fibre intake and change in postprandial 2-h glucose levels, showing a metabolic benefit beyond 14 g and a plateau beyond 25 g of total insoluble fibre per day. 2-h glucose levels improved significantly stronger in both upper tertiles (−0.9 [−1.6;−0.2] mmol/l, p = 0.047, and −0.6 [−1.6;0.3] mmol/l, p = 0.010) compared to the lowest tertile (0.1 [−1.2;1.1] mmol/l), also when adjusted for changes in bodyweight. Subjects with the highest fibre intake showed superior effects on fasting and postprandial insulin resistance, hepatic insulin clearance, leucocyte count and fatty liver index. Conclusions: Extending the knowledge on the benefits of insoluble oat hulls fibre, our post hoc analysis demonstrates a dose effect for glycaemia and associated metabolic markers. Further research is needed in order to replicate our findings in larger trials. [ABSTRACT FROM AUTHOR]

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70–100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised. [ABSTRACT FROM AUTHOR]

Reynolds number effects on the aerodynamics of the moderately thick NACA 0021 airfoil were experimentally studied by means of surface-pressure measurements. The use of a high-pressure wind tunnel allowed for variation of the chord Reynolds number over a range of 5.0 × 10 5 ≤ R e c ≤ 7.9 × 10 6 . The angle of attack was incrementally increased and decreased over a range of 0 ∘ ≤ α ≤ 40 ∘ , spanning both the attached and stalled regime at all Reynolds numbers. As such, attached and separated conditions, as well as the static stall and reattachment processes were studied. A fundamental change in the flow behavior was observed around R e c = 2.0 × 10 6 . As the Reynolds number increased beyond this value, the stall type gradually shifted from trailing-edge stall to leading-edge stall. The stall angle and the maximum lift coefficient increased with Reynolds number. Once the flow was separated, the separation point moved upstream, and the suction peak decreased in magnitude with increasing Reynolds number. Two distinct types of hysteresis in reattachment were observed. The data from this study are publicly available at https://doi.org/10.34770/9mv0-zd78. [ABSTRACT FROM AUTHOR]

The continuum of growth hormone (GH)-IGF-I axis defects extends from severe to mild GH deficiency, through short stature disorders of undefined aetiology, to GH insensitivity disorders which can also be mild or severe. This group of defects comprises a spectrum of endocrine, biochemical, phenotypic and genetic abnormalities. The extreme cases are generally easily diagnosed because they conform to well-studied phenotypes with recognised biochemical features. The milder cases of both GH deficiency and GH insensitivity are less well defined and also overlap with the group of short stature conditions, labelled as idiopathic short stature (ISS). In this review the continuum model, which plots GH sensitivity against GH secretion, will be discussed. Defects causing GH deficiency and GH insensitivity will be described, together with the use of a diagnostic algorithm, designed to aid investigation and categorisation of these defects. The continuum will also be discussed in the context of growth-promoting endocrine therapy. [ABSTRACT FROM AUTHOR]

This review describes a cellular adaptive stress signalling roadmap connecting the 1H magnetic resonance spectroscopy (MRS) total choline peak at 3.2 ppm (tCho) to cancer response after targeted therapy (TT). Recent research on cell signalling, tCho metabolism, and TT of cancer has been retrospectively re-examined. Signalling research describes how the unfolded protein response (UPR), a major stress signalling network, transduces, regulates, and rewires the total membrane turnover in different cancer hallmarks after a TT stress. In particular, the UPR signalling maintains or increases total membrane turnover in all pro-survival hallmarks, whilst dramatically decreases turnover during apoptosis, a pro-death hallmark. Recent research depicts the TT-induced stress as a crucial event responsible for interrupting UPR pro-survival pathways, leading to an UPR-mediated cell death. The 1H-MRS tCho resonance represents the total mobile precursors and products during the enzymatic modification of phosphatidylcholine membrane abundance. The tCho profile represents a biomarker that noninvasively monitors TT-induced enzymatic changes in total membrane turnover in a wide variety of existing and new anticancer treatments targeting specific layers of the UPR signalling network. Our overview strongly suggests further evaluating and validating the 1H-MRS tCho peak as a powerful noninvasive imaging biomarker of cancer response in TT clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: During the COVID-19 pandemic, there have been particular concerns regarding the related impact on specialist tumour services. Neuroendocrine tumour (NET) services are delivered in a highly specialised setting, typically delivered in a small number of centres that fulfil specific criteria as defined by the European Neuroendocrine Tumour Society (ENETS). We aimed to address the COVID-19-related impact on specialist NET tumour services in England and other countries. Methods: Electronic survey addressing patient access and delivery of care distributed to all ENETS Centres of Excellence (CoE) in England and matching number of ENETS CoE elsewhere. Semi-quantitative and qualitative analyses of survey responses were performed. Results: Survey response of ENETS CoE in England was 55% (6/11). Responses from six non-UK ENETS CoE elsewhere were received and analysed in a similar manner. Relevant disruption of various NET services was noted across all responding Centres, which included delayed patient appointments and investigations, reduced availability of treatment modalities including delayed surgical treatment and a major negative impact on research activities. The comparison between English and non-UK ENETS CoE suggested that the former had significantly greater concerns related to future research funding (p = 0.014), whilst having less disruption to multidisciplinary meetings (p = 0.01). A trend was also noted towards virtual patient appointments in ENETS CoE in England vs. elsewhere (p = 0.092). Conclusions: Restoration of highly specialised NET services following COVID-19 and planning for future service delivery and research funding must take account of the severe challenges encountered during the pandemic. [ABSTRACT FROM AUTHOR]

Three new 2-pyrral amino acid Schiff base palladium (II) complexes were synthesized, characterized and their activity against six bacterial species was investigated. The ligands: Potassium 2-pyrrolidine-L-methioninate (L1), Potassium 2-pyrrolidine-L-histidinate (L2) and Potassium 2-pyrrolidine-L-tryptophanate (L3) were synthesized and reacted with dichloro(1,5-cyclooctadiene)palladium(II) to form new palladium (II) complexes C1, C2 and C3, respectively. 1H NMR, FTIR, UV–Vis, elemental analysis and conductivity measurements were used to characterize the products. The antibacterial activities of the compounds were evaluated against Gram-positive Staphylococcus aureus (S. aureus, ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591), Staphylococcus epidermidis (S. epidermidis, ATCC 12228) and Streptococcus pyogenes (S. pyogenes, ATCC 19615) and, gram-negative Pseudomonas aeruginosa (P. aeruginosa, ATCC 27853) and Klebsiella pneumoniae (K. pneumoniae, ATCC 13883) using the agar well diffusion assay and microtitre plate serial dilution method. The palladium complexes were active against the selected bacteria with the imidazole ring containing complex C2 and indole heterocyclic ring containing complex C3 showing the highest activity. [ABSTRACT FROM AUTHOR]

Background/aims: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL). Methods: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC. HRQoL EORTC-QLC-C30 questionnaires and cross-sectional imaging data were prospectively collected. Age- and sex-matched healthy controls were recruited for HRQoL analysis' validation. Results: We included 166 patients (119 women [71.2%]: mean age at baseline: 31 ± 16 years). Mean follow-up was 50.9 ± 54 months. Most patients (152 [92%]) had tumors ≤20 mm in size. Fifty-eight patients (34.9%) underwent pRHC that in final analysis was regarded as an overtreatment in 38/58 (65.5%). In multivariable analysis, tumor size >20 mm was the only independent predictor for lymph node (LN) involvement (p = 0.002). No mortality was reported, whereas 2-, 5- and 10-year recurrence-free survival in patients subjected to postoperative cross-sectional imaging (n = 136) was 98.5%, 97.8%, and 97.8%, respectively. Global HRQoL was not significantly impaired in patients with WD-ANEN compared with age- and sex-matched healthy individuals (median scores 0.83[0.08−1] vs 0.83[0.4−1], respectively; p = 0.929). Among patients with WD-ANEN impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group. Conclusions: WD-ANEN is a low-malignant neoplasm with unconfirmed associated mortality, low recurrence rate, and overall preserved HRQoL. pRHC comes at a price of excessive surgery, functional HRQoL issues, and diarrhea. The value per se of a prophylactic surgical approach to patients with WD-ANENs <20 mm is challenged. [ABSTRACT FROM AUTHOR]

Mineral precipitation can drastically alter a reservoir's ability to transmit mass and energy during various engineering/natural subsurface processes, such as geothermal energy extraction and geological carbon dioxide sequestration. However, it is still challenging to explain the relationships among permeability, porosity, and precipitation patterns in reservoirs, particularly in fracture-dominated reservoirs. Here, we investigate the pore-scale behavior of single-species mineral precipitation reactions in a fractured porous medium, using a phase field lattice-Boltzmann method. Parallel to the main flow direction, the medium is divided into two halves, one with a low-permeability matrix and one with a high-permeability matrix. Each matrix contains one flow-through and one dead-end fracture. A wide range of species diffusivity and reaction rates is explored to cover regimes from advection- to diffusion-dominated, and from transport- to reaction-limited. By employing the ratio of the Damköhler (Da) and the Peclet (Pe) number, four distinct precipitation patterns can be identified, namely (1) no precipitation (Da/Pe < 1), (2) near-inlet clogging (Da/Pe > 100), (3) fracture isolation (1 < Da/Pe < 100 and Pe > 1), and (4) diffusive precipitation (1 < Da/Pe < 100 and Pe < 0.1). Using moment analyses, we discuss in detail the development of the species (i.e., reactant) concentration and mineral precipitation fields for various species transport regimes. Finally, we establish a general relationship among mineral precipitation pattern, porosity, and permeability. Our study provides insights into the feedback loop of fluid flow, species transport, mineral precipitation, pore space geometry changes, and permeability in fractured porous media. [ABSTRACT FROM AUTHOR]

Fluid flow in rough fractures and the coupling with the mechanical behaviour of the fractures pose great difficulties for numerical modeling approaches due to complex fracture surface topographies, the non-linearity of hydro-mechanical processes and their tightly coupled nature. To this end, we have adapted a fictitious domain method to enable the simulation of hydro-mechanical processes in fracture intersections. The main characteristic of the method is the immersion of the fracture, modelled as a linear elastic solid, in the surrounding computational fluid domain, modelled with the incompressible Navier-Stokes equations. The fluid and the solid problems are coupled with variational transfer operators. Variational transfer operators are also used to solve contact within the fracture using a dual mortar approach and to generate problem-specific fluid meshes. With respect to our applications, the key features of the method are the usage of different finite element discretizations for the solid and the fluid problem and the automatically generated representation of the fluid-solid boundary. We demonstrate that the presented methodology resolves small-scale roughness on the fracture surface, while capturing fluid flow field changes during mechanical loading. Starting with 2D/3D benchmark simulations of intersected fractures, we end with an intersected fracture composed of complex fracture surface topographies, which are in contact under increasing loads. The contributions of this article are as follows: (1) the application of the fictitious domain method to study flow in fractures with intersections, (2) a mortar-based contact solver for the solid problem, (3) generation of problem-specific grids using the geometry information from the variational transfer operators. [ABSTRACT FROM AUTHOR]

Background (or purpose): Nivolumab has been shown to be effective for the treatment of second-line mRCC. The present study has investigated the effectiveness and safety of nivolumab in real-world Eastern Spanish patients with advanced mRCC at TKI progression. Patients and methods: A retrospective review of mRCC patients treated with nivolumab as a second-line treatment was performed. Analyzed variables included age, sex, ECOG (quality of life scale designed by the Eastern Cooperative Oncology Group), histology, nephrectomy, location of metastases, number of metastasis locations, previous treatments, analytical data from the standard blood count and biochemistry, and response to treatment. Results: 98 patients from 18 sites in Spain were retrospectively reviewed. The majority of patients were male (75%), had ECOG 0–1 (90.6%), had no brain metastasis (91.4%), had undergone one prior systemic regimen (94.3%), and were current/former smokers (97.1%). Fourteen patients (13.1%) had non-clear cell histology, seven (7.1%) had poor-IMDC prognostic group characteristics, 13 patients (13.1%) had liver metastasis and 35 (35.7%) had bone lesions. All patients received prior systemic therapy (63.3% sunitinib, 34.7% pazopanib). During the study, a median of eight doses of nivolumab was given (range 2–62) and 11 patients received more than 12 doses. Eleven patients (11.2%) received nivolumab as a third or fourth line of treatment. Median duration of therapy was 3.6 months (range 0.5–29.3). Confirmed response rate was 25%. Median progression free survival was 7.8 months (range 1.2–12.1). Median overall survival was 16.3 months (range 1.7–29.3). After discontinuation of treatment, 27.58% of the patients received subsequent systemic cancer therapy. Side effects were mostly grade 1–2 (7.2% had hypothyroidism and 6.2% liver toxicity, 4% had nephritis and 2% hypophysitis). Two cases of grade 3–4 adverse events (2%) were reported. Conclusion: Benefit/risk profile of nivolumab in Eastern-Spanish real-world population with mRCC after tyrosine-kinase inhibitors was consistent with prior real-life studies reported as well as pivotal study. [ABSTRACT FROM AUTHOR]

Thermal spallation drilling is a contact-less means of borehole excavation that works by exposing a rock surface to a high-temperature jet flame. In this study, we investigate crucial factors for the success of such thermal drilling operations using numerical simulations of the thermomechanical processes leading to rock failure at the borehole surface. To that end, we integrate a model developed for spalling failure with our thermomechanical simulations. In particular, we consider the role of material heterogeneities, maximum jet-flame temperature and maximum jet-flame temperature rise time on the onset of inelastic deformation and subsequent damage. We further investigate differences in energy consumption for the studied system configurations. The simulations highlight the importance of material composition, as thermal spallation is favored in fine-grained material with strong material heterogeneity. The model is used to test the relationship between the jet-flame temperature and the onset of thermal spallation. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58–7.12)), HIV positivity (OR = 2.22(1.32–3.73)) and living in a more rural area (OR = 1.38(1.01–1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10−09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10−12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10−44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission. Disease prognosis after infection with Kaposi's sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission. [ABSTRACT FROM AUTHOR]

When water is injected into a fracture-dominated reservoir that is cooler or hotter than the injected water, the reservoir permeability is expected to be altered by the injection-induced thermo-mechanical effects, resulting in the redistribution of fluid flow in the reservoir. These effects are important to be taken into account when evaluating the performance and lifetime particularly of Enhanced Geothermal Systems (EGS). In this paper, we compare the results from two dye tracer tests, conducted before (at ambient temperature of 13 ∘ C ) and during the injection of 45 ∘ C hot water into a fractured crystalline rock at the Grimsel Test Site in Switzerland. Conducting a moment analysis on the recovered tracer residence time distribution (RTD) curves, we observe, after hot water injection, a significant decrease in the total tracer recovery. This recovery decrease strongly suggests that fluid flow was redistributed in the studied rock volume and that the majority of the injected water was lost to the far-field. Furthermore, using temperature measurements, obtained from the same locations as the tracer RTD curves, we conceptualize an approach to estimate the fracture surface area contributing to the heat exchange between the host rock and the circulating fluid. Our moment analysis and simplified estimation of fracture surface area provide insights into the hydraulic properties of the hydraulically active fracture system and the changes in fluid flow. Such insights are important to assess the heat exchange performance of a geothermal formation during fluid circulation and to estimate the lifetime of the geothermal formation, particularly in EGS. [ABSTRACT FROM AUTHOR]

During reactive transport modeling, the computing cost associated with chemical equilibrium calculations can be 10 to 10,000 times higher than that of fluid flow, heat transfer, and species transport computations. These calculations are performed at least once per mesh cell and once per time step, amounting to billions of them throughout the simulation employing high-resolution meshes. To radically reduce the computing cost of chemical equilibrium calculations (each requiring an iterative solution of a system of nonlinear equations), we consider an on-demand machine learning algorithm that enables quick and accurate prediction of new chemical equilibrium states using the results of previously solved chemical equilibrium problems within the same reactive transport simulation. The training operations occur on-demand, rather than before the start of the simulation when it is not clear how many training points are needed to accurately and reliably predict all possible chemical conditions that may occur during the simulation. Each on-demand training operation consists of fully solving the equilibrium problem and storing some key information about the just computed chemical equilibrium state (which is used subsequently to rapidly predict similar states whenever possible). We study the performance of the on-demand learning algorithm, which is mass conservative by construction, by applying it to a reactive transport modeling example and achieve a speed-up of one or two orders of magnitude (depending on the activity model used). The implementation and numerical tests are carried out in Reaktoro (reaktoro.org), a unified open-source framework for modeling chemically reactive systems. [ABSTRACT FROM AUTHOR]

To improve the economics and viability of accessing deep georesources, we propose a combined thermo–mechanical drilling (CTMD) method, employing a heat source to facilitate the mechanical removal of rock, with the aim of increasing drilling performance and thereby reducing the overall costs, especially for deep wells in hard rocks. In this work, we employ a novel experiment setup to investigate the main parameters of interest during the interaction of a cutter with the rock material, and we test untreated and thermally treated sandstone and granite, to understand the underlying rock removal mechanism and the resulting drilling performance improvements achievable with the new approach. We find that the rock removal process can be divided into three main regimes: first, a wear-dominated regime, followed by a compression-based progression of the tool at large penetrations, and a final tool fall-back regime for increasing scratch distances. We calculate the compressive rock strengths from our tests to validate the above regime hypothesis, and they are in good agreement with literature data, explaining the strength reduction after treatment of the material by extensive induced thermal cracking of the rock. We evaluate the new method's drilling performance and confirm that thermal cracks in the rock can considerably enhance subsequent mechanical rock removal rates and related drilling performance by one order of magnitude in granite, while mainly reducing the wear rates of the cutting tools in sandstone. [ABSTRACT FROM AUTHOR]

A series of short events, called A-phases, can be observed in the human electroencephalogram (EEG) during Non-Rapid Eye Movement (NREM) sleep. These events can be classified in three groups (A1, A2, and A3) according to their spectral contents, and are thought to play a role in the transitions between the different sleep stages. A-phase detection and classification is usually performed manually by a trained expert, but it is a tedious and time-consuming task. In the past two decades, various researchers have designed algorithms to automatically detect and classify the A-phases with varying degrees of success, but the problem remains open. In this paper, a different approach is proposed: instead of attempting to design a general classifier for all subjects, we propose to train ad-hoc classifiers for each subject using as little data as possible, in order to drastically reduce the amount of time required from the expert. The proposed classifiers are based on deep convolutional neural networks using the log-spectrogram of the EEG signal as input data. Results are encouraging, achieving average accuracies of 80.31% when discriminating between A-phases and non A-phases, and 71.87% when classifying among A-phase sub-types, with only 25% of the total A-phases used for training. When additional expert-validated data is considered, the sub-type classification accuracy increases to 78.92%. These results show that a semi-automatic annotation system with assistance from an expert could provide a better alternative to fully automatic classifiers. Graphical abstract A/N Deep Learning Classifier. [ABSTRACT FROM AUTHOR]

Faba bean (Vicia faba L.) is a pulse crop of high nutritional value and high importance for sustainable agriculture and soil protection. With the objective of identifying gene-based SNPs, transcriptome sequencing was performed in order to reduce faba bean genome complexity. A set of 1,819 gene-based SNP markers polymorphic in three recombinant line populations was selected to enable the construction of a high-density consensus genetic map encompassing 1,728 markers well distributed in six linkage groups and spanning 1,547.71 cM with an average inter-marker distance of 0.89 cM. Orthology-based comparison of the faba bean consensus map with legume genome assemblies highlighted synteny patterns that partly reflected the phylogenetic relationships among species. Solid blocks of macrosynteny were observed between faba bean and the most closely-related sequenced legume species such as pea, barrel medic or chickpea. Numerous blocks could also be identified in more divergent species such as common bean or cowpea. The genetic tools developed in this work can be used in association mapping, genetic diversity, linkage disequilibrium or comparative genomics and provide a backbone for map-based cloning. This will make the identification of candidate genes of interest more efficient and will accelerate marker-assisted selection (MAS) and genomic-assisted breeding (GAB) in faba bean. [ABSTRACT FROM AUTHOR]

Background: Monocarboxylate transporter 1 (MCT1) is a regulator of cell metabolism and a therapeutic target for cancer treatment. Understanding the changes in tumour function accompanying MCT1 inhibition will better characterise the anti-tumour effects of MCT1 inhibitors, potentially enabling the identification of pharmacodynamic biomarkers for the clinical development of these agents.Methods: We assessed the impact of the MCT1 inhibitor AZD3965 on tumour metabolism and immune cell infiltration as key determinants of tumour biological function in the MCT1-dependent Raji B cell lymphoma model.Results: Treatment of Raji xenograft-bearing severe combined immunodeficiency mice with AZD3965 led to inhibition of tumour growth paralleled with a decrease in tumour choline, as detected by non-invasive in vivo proton nuclear magnetic resonance spectroscopy. This effect was attributed to inhibition of phosphocholine de novo synthesis following decreased choline kinase α protein and messenger RNA expression that correlated with the AZD3965-induced build-up in intracellular lactate. These changes were concomitant with increased tumour immune cell infiltration involving dendritic and natural killer cells.Conclusions: Our data provide new insights into the metabolic and cellular changes that occur in the tumour microenvironment following MCT1 blockade, which may contribute to the anti-tumour activity of AZD3965 and could have potential as pharmacodynamic biomarkers of MCT1 inhibition. [ABSTRACT FROM AUTHOR]

Computerized Perimetry (CP) is one of the clinical tests commonly used to evaluate peripheral vision and monitor the progress of eye diseases such as glaucoma. The aim of CP is to determine retinal sensitivity using luminous stimuli of variable intensity at different positions of the visual field. In modern campimetry devices, patients must respond to each perceived stimulus by pressing a button; however, this characteristic makes the test more susceptible to spurious and erroneous interpretations due to tiredness, lack of concentration, or device design flaws. This work presents an alternative paradigm for automatically assessing stimulus perception through a low-cost eye tracker and a computer monitor. We tested the preliminary version of the paradigm among eight subjects and obtained favorable results. In conclusion, our eye-tracking paradigm tool could help design more reliable visual field tests using low-cost portable equipment. [ABSTRACT FROM AUTHOR]

Background: BRAF inhibitors, such as vemurafenib, have shown efficacy in BRAF-mutant melanoma treatment but acquired-resistance invariably develops. Unveiling the potential vulnerabilities associated with vemurafenib resistance could provide rational strategies for combinatorial treatment.Methods: This work investigates the metabolic characteristics and vulnerabilities of acquired resistance to vemurafenib in three generated BRAF-mutant human melanoma cell clones, analysing metabolic profiles, gene and protein expression in baseline and nutrient withdrawal conditions. Preclinical findings are correlated with gene expression analysis from publicly available clinical datasets.Results: Two vemurafenib-resistant clones showed dependency on lipid metabolism and increased prostaglandin E2 synthesis and were more responsive to vemurafenib under EGFR inhibition, potentially implicating inflammatory lipid and EGFR signalling in ERK reactivation and vemurafenib resistance. The third resistant clone showed higher pyruvate-carboxylase (PC) activity indicating increased anaplerotic mitochondrial metabolism, concomitant with reduced GLUT-1, increased PC protein expression and survival advantage under nutrient-depleted conditions. Prostaglandin synthase (PTGES) expression was inversely correlated with melanoma patient survival. Increases in PC and PTGES gene expression were observed in some patients following progression on BRAF inhibitors.Conclusions: Altogether, our data highlight heterogeneity in metabolic adaptations during acquired resistance to vemurafenib in BRAF-mutant melanoma, potentially uncovering key clinically-relevant mechanisms for combinatorial therapeutic targeting. [ABSTRACT FROM AUTHOR]

An assisted method to segment Visceral Adipose Tissue (VAT) and Subcutaneous Adipose Tissue (SAT) from Magnetic Resonance Imaging (MRI) slices is presented. The segmentation process, called shape-based segmentation, consists in three main steps: 1) to draw a series of closed curves at different slices that separates the abdominal structures of interest, 2) to generate a 3D model from the closed curves for each abdominal structure by using shape-based interpolation and 3) to apply a segmentation algorithm to define the adipose tissue. The 3D models considerably simplify the problem since the abdominal structures are separated, and in turn, this reduces the possibility of large segmentation errors. In addition, a fully automatic segmentation procedure was also implemented. Twenty slices of MRI at the abdominal region for each of twelve subjects were analysed. The results of the shape-based and automatic segmentation were compared with the expert segmentation carried out in the slice located at the umbilicus level. Correlation Coefficient (CC) and volume error (VE) were used as performance measures. The comparison between the expert and shape-based segmentation for SAT yielded results of CC= 0.974 and VE=-0.01 ± 5.8 cm3, while for VAT the performance indexes were CC= 0.993 and VE= 0.9 ± 1.8 cm3. The results suggest that the shape-based segmentation provides an accurate and simple assessment of the abdominal adiposity with minimal human intervention and it could be used as a simple tool in clinics. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects. Methods: Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q0) and sensitivity to price (essential value, EV), derived. Results: Rimcazole dose-dependently decreased Q0 and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. Conclusions: Though the drug combinations only replicated rimcazole's effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade. [ABSTRACT FROM AUTHOR]

Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5–0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0–80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5–12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14–0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels. [ABSTRACT FROM AUTHOR]

Hydro-mechanical processes in rough fractures are highly non-linear and govern productivity and associated risks in a wide range of reservoir engineering problems. To enable high-resolution simulations of hydro-mechanical processes in fractures, we present an adaptation of an immersed boundary method to compute fluid flow between rough fracture surfaces. The solid domain is immersed into the fluid domain and both domains are coupled by means of variational volumetric transfer operators. The transfer operators implicitly resolve the boundary between the solid and the fluid, which simplifies the setup of fracture simulations with complex surfaces. It is possible to choose different formulations and discretization schemes for each subproblem and it is not necessary to remesh the fluid grid. We use benchmark problems and real fracture geometries to demonstrate the following capabilities of the presented approach: (1) resolving the boundary of the rough fracture surface in the fluid; (2) capturing fluid flow field changes in a fracture which closes under increasing normal load; and (3) simulating the opening of a fracture due to increased fluid pressure. [ABSTRACT FROM AUTHOR]

Fractures are conduits that can enable fast advective transfer of (fluid, solute, reactant, particle, etc.) mass and energy. Such fast transfer can significantly affect pore-scale physico-chemical processes, which can in turn affect macroscopic mass and energy transport characteristics. Here, flooding experiments are conducted in a well-characterized fractured porous medium, manufactured by 3D printing. Given steady-state flow conditions, the micro-structure of the two-dimensional pore fluid flow field is delineated to resolve fluid velocities on the order of a sub-millimeter per second. We demonstrate the capabilities of a new temporo-ensemble particle image velocimetry method by maximizing its spatial resolution, employing in-line illumination. This method is advantageous as it is capable of minimizing the number of pixels, required for velocity determinations, down to one pixel, thereby enabling resolving high spatial resolutions of velocity vectors in a large field of view. While the main goal of this study is to introduce a novel experimental and velocimetry framework, this new method is then applied to specifically improve the understanding of fluid flow through fractured porous media. Histograms of measured velocities indicate log-normal and Gaussian-type distributions of longitudinal and lateral velocities in fractures, respectively. The magnitudes of fluid velocities in fractures and the flow interactions between fractures and matrices are shown to be influenced by the permeability of the background matrix and the orientation of the fractures. [ABSTRACT FROM AUTHOR]

Advanced solid-state quantum bits (qubits) are likely to require a variety of dielectrics for wiring crossovers, substrates, and Josephson junctions. Microwave superconducting resonators are an excellent tool for measuring the internal dielectric loss of materials. We report the dielectric loss of boron-based dielectric films using a microwave coplanar waveguide (CPW) resonator with heterostructure geometry. Power-dependent internal quality factors of magnetron-sputtered boron carbide ( B 4 C ) and boron nitride (BN) were measured and are compared to silicon oxide ( SiO 2 ), a common material used in wiring crossovers. The internal dielectric loss due to two-level systems for B 4 C , and BN is less than silicon dioxide ( SiO 2 ), which demonstrates the existence of low-loss sputtered materials. We also found that niobium (Nb) CPW resonators suffer a decrease in internal quality factor after deposition of B 4 C at temperatures above 150 ∘ C . This result is consistent with the idea that the oxidation of the surface of the superconducting metal can contribute to loss in a device. [ABSTRACT FROM AUTHOR]

Purpose: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). Methods: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. Results: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4–395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589–14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14–463) months. Conclusions: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes. [ABSTRACT FROM AUTHOR]