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Abstract Diseases caused by S. pneumoniae are the leading cause of child mortality. As antibiotic resistance of S. pneumoniae is rising, vaccination remains the most recommended solution. However, the existing pneumococcal polysaccharides vaccine (Pneumovax® 23) proved only to induce T-independent immunity, and strict cold chain dependence of the protein conjugate vaccine impedes its promotion in developing countries, where infections are most problematic. Affordable and efficient vaccines against pneumococcus are therefore in high demand. Here, we present an intranasal vaccine Lipo+CPS12F&αGC, containing the capsular polysaccharides of S. pneumoniae 12F and the iNKT agonist α-galactosylceramide in cationic liposomes. In BALB/cJRj mice, the vaccine effectively activates iNKT cells and promotes B cells maturation, stimulates affinity-matured IgA and IgG production in both the respiratory tract and systemic blood, and displays sufficient protection both in vivo and in vitro. The designed vaccine is a promising, cost-effective solution against pneumococcus, which can be expanded to cover more serotypes and pathogens.

Abstract Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming an intratumoral sustained drug release depot that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues, consequently generating systemic anticancer immunoreactivity. CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-β inhibitor in preclinical tumor models in female mice.

This article focuses on a learning objective, as part of a teacher education course at a Swedish university, where student teachers should be able to discuss their own professional development and identify further development needs. Since both research and policy documents highlight professional development as an important part of teacher education, it is important to study professional development from the perspective of student teachers. The theoretical starting point is Communities of Practice (CoP), and the study focuses on knowledge and learning within a social community. Ten subject teacher students and six vocational teacher students are interviewed about their descriptions of what the professional development for teachers in teacher education means for them, which results in six prominent themes: 1) the developmentof identity formation, 2) the development of subject specific and vocational knowledge, 3) the development of leadership, 4) the development of relationship-building, 5) the development of knowledge about policy documents, laws, rules and regulations, 6) the development in relation to changes in the society. Despite common denominators in the students’ descriptions of professional development, there are also nuanced differences that can be understood by positioning actors about the (vocational) teacher education community. The vocational teacher students frequently connect their professional knowledge to industry and working life, whereas the subject teacher students often connect their subject knowledge to university courses and research. Both the vocational teacher students and the subject teacher students in the study describe that they need to stay up-to-date and continue developing their competence in pedagogy. However, the vocational teacher students specifically highlight the need for pedagogical knowledge within the school environment, rather than in the context of working life and workshop settings. This may be because some vocational teacher students are accustomed to training and teaching interns in these environments as part of their professional practice.

Abstract The Scheil–Gulliver equation is essential for assessing solid fractions during alloy solidification in materials science. Despite the prevalent use of the Calculation of Phase Diagrams (CALPHAD) method, its computational intensity and time are limiting the simulation efficiency. Recently, Artificial Intelligence has emerged as a potent tool in materials science, offering robust and reliable predictive modeling capabilities. This study introduces an ensemble‐based method that has the potential to enhance the prediction of the partitioning coefficient (k) in the Scheil equation by inputting various alloy compositions. The findings demonstrate that this approach can predict the temperature and solid fraction at the eutectic temperature with an accuracy exceeding 90%, while the accuracy for k prediction surpasses 70%. Additionally, a case study on a commercial alloy revealed that the model's predictions are within a 5°C deviation from experimental results, and the predicted solid fraction at the eutectic temperature is within a 15% difference of the values obtained from the CALPHAD model.

Abstract The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

"The healing link in an errant chain of thought". Modernism, avant-garde, and the critically affirmative irony of bob hund bob hund could be called a «post-rock band» that investigates what it really means to be a rock band – or, as they call themselves: a pop orchestra. How do you put together the given components drum, bass, guitar and keyboard in constellations that make something new appear? In trying to respond to this question, this article points to bob hund’s roots in modernist avant-garde aesthetics, and examines what such winding connections between different traditions might mean. Aesthetic practices such as decontextualization, irony, anacoluthon wordplay, and lists change when they are used in new and different historical contexts. If high modernism was reduced to form, and Duchampian neodadaism to lifestyle choices, then bob hund opens new possibilities for aesthetic practices in today's anthropocenic hypercapitalism.

Johan Jönsons poesi är politisk, konceptuell, lyrisk, experimentell med mera, kort sagt: den är mycket (också volymmässigt). Men samtidigt är den inte allt detta. Den vrider och vänder, den förnekar och använder – alla dessa förståelser av vad poesi är eller gör. Därigenom skriver den in sig i den kritiskt reflekterande poetiska traditionen, men på sitt speciella sätt. Den här artikeln undersöker hur Jönsons poesi ställer och förhåller sig till frågor som: ”Tänker litteraturen? Upplever den? Hur? Vad?” Artikeln utforskar dessa frågor genom att noga följa användningen av punkter och deras effekter. Vanligtvis märker vi inte punkter när vi läser, eftersom kommunikation fungerar när vi inte lägger märke till mediet. Men som punktens historia visar är den inte oskyldig. Den underlättar förståelsen av en text, men den styr också förståelsen av en text. För de medeltidsforskare som förespråkade dess införande, tillsammans med andra skiljetecken, gällde det att kontrollera att läsaren läste doktrinen korrekt. Jönsons användning av punkter hindrar istället viljan att kontrollera. De dekontextualiserar och avbryter kommunikationen, från det att de stör ögats rörelse över boksidan till att de punkterar förståelsen. De markeras, och de markerar, olika. Våra vanliga sätt att se på avsikt, handlingskraft, mening och förståelse punkteras av en poetisk upplevelse som inte längre är knuten till mänskligt agentskap och kontroll.

Abstract Background Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. Methods The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. Discussion This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. Trial registration EudraCT no. 2021–000069-34. ClinicalTrials.gov NCT04966559. Registered on July 8, 2021.

Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.

Aluminum-based composites provide tribological performance and thermophysical properties that, combined with being lightweight, are suitable for their application in automotive brake discs. Aluminum alloys allow the use of secondary materials to produce composites, with the drawback of several elements, impurities, and oxides that can harm the mechanical and thermophysical properties. This preliminary study explored the mechanical and thermophysical performance of a composite material produced with a secondary matrix alloy. Overall, the results are promising, with a minimal decrease in mechanical and thermophysical properties despite clustered silicon carbide particles in the composite with the secondary matrix. The challenges in effectively dispersing carbides in the melt seem linked to aluminum oxides, and future microstructural investigations will aim to clarify this aspect.

Abstract Background Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). Methods In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. Results Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. Conclusions ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. Trial registration: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

The production of meltwater from glacier ice, which is exposed at the margins of land ice during the summer, is responsible for a large proportion of glacier mass loss. The rate of meltwater production from glacier ice is especially sensitive to its physical structure and chemical composition which combine to determine the albedo of glacier ice. However, the optical properties of near-surface glacier ice are not well known since most prior work has focused on laboratory-grown ice or deep cores. Here, we demonstrate a measurement technique based on diffuse propagation of nanosecond-duration laser pulses in near-surface glacier ice that enables the independent measurement of the scattering and absorption coefficients, allowing for a complete description of the processes governing radiative transfer. We employ a photon-counting detector to overcome the high losses associated with diffuse optics. The instrument is highly portable and rugged, making it optimally suited for deployment in remote regions. A set of measurements taken on Crook and Collier Glaciers, Oregon, serves as a demonstration of the technique. These measurements provide insight into both physical structure and composition of near-surface glacier ice and open new avenues for the analysis of light-absorbing impurities and remote sensing of the cryosphere.

Abstract Fatty liver disease has mainly been characterized under fasting conditions. However, as the liver is essential for postprandial homeostasis, identifying postprandial disturbances may be important. Here, we investigated postprandial changes in markers of metabolic dysfunction between healthy individuals, obese individuals with non‐alcoholic fatty liver disease (NAFLD) and patients with cirrhosis. We included individuals with biopsy‐proven NAFLD (n = 9, mean age 50 years, mean BMI 35 kg/m2, no/mild fibrosis), cirrhosis with hepatic steatosis (n = 10, age 62 years, BMI 32 kg/m2, CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2), randomized 1:1 to fasting or standardized mixed meal test (postprandial). None of the patients randomized to mixed meal test had type 2 diabetes (T2D). Peripheral blood was collected for 120 min. After 60 min, a transjugular liver biopsy and liver vein blood was taken. Plasma levels of glucose, insulin, C‐peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured. Postprandial peak glucose and C‐peptide were significantly increased in NAFLD, and cirrhosis compared with healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia as a potential sign of glucagon resistance. FGF21 was increased in NAFLD and cirrhosis independent of sampling from the liver vein versus peripheral blood. Glucagon levels were higher in the liver vein compared with peripheral blood. Patients with NAFLD and cirrhosis without T2D showed impaired glucose tolerance, hyperinsulinemia, and hyperglucagonemia after a meal compared to healthy individual. Postprandial characterization of patients with NAFLD may be important to capture their metabolic health.

Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We demonstrated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues (and primary renal proximal tubule epithelial (RPTEC) cells). We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate 14q32 miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of a 14q32 miRNA. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431-5p, miR-432-5p, miR-127-3p, and miR-433-3p) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.

Lightweight SiC-particle-reinforced aluminum composites have the potential to replace cast iron in brake discs, especially for electric vehicles. This study investigates the effect of SiC particle size and matrix alloy composition on the resulting transfer efficiency and particle distribution. The performance of a specially designed stirring head was studied using a water model, and the stirring head conditions were assessed to understand the particle transfer and dispersion mechanisms in the molten aluminum. The standard practice of thermal pre-treatment promotes the wetting of the reinforcing particles and commonly causes clustering before the addition to the melt. This early clustering affects the transfer efficiency and particle dispersion, where their interaction with the melt top-surface oxide skin plays an important role. In addition, the transfer efficiency was linked to the particle size and the chemical composition of the matrix alloy. Smaller particles aggravated the degree of clustering, and the addition of rare earth elements as alloying elements in the matrix alloy affected the particle dispersion. The stirring parameters should be selected to ensure cluster disruption when the carbides are added to the melt.

Aluminium can be essential in reducing climate impacts as weight reduction is critical. Rheocasting is getting more and more attention from the electronics and automotive industries. The solid fraction in Rheocasting determines the processing outcome. The RheoMetal process is one of the leading processes with the most significant deviation from equilibrium, making presetting the slurry-making parameters difficult. A deeper analysis of the physics of the solid fraction deviation from equilibrium is made based on literature data using a simplistic mathematical model. The developed model confirms that the process is far from equilibrium and that the growth conditions of the freeze-on layer on the cooling agent used in the process determine the slurry temperature and cause the formation of excess solid fraction.

The coexistence of diverse services with heterogeneous requirements is a fundamental feature of 5G. This necessitates efficient Radio Access Network (RAN) slicing, defined as sharing of the wireless resources among diverse services while guaranteeing their throughput, timing, and/or reliability requirements. In this paper, we investigate RAN slicing for an uplink scenario in the form of multiple access schemes for two user types: (1) broadband users with throughput requirements and (2) intermittently active users with timing requirements, expressed as either Latency-Reliability (LR) or Peak Age of Information (PAoI). Broadband users transmit data continuously, hence, are allocated non-overlapping parts of the spectrum. We evaluate the trade-offs between the achievable throughput of a broadband user and the timing requirements of an intermittent user under Orthogonal Multiple Access (OMA) and Non-Orthogonal Multiple Access (NOMA), considering capture. Our analysis shows that NOMA, in combination with packet-level coding, is a superior strategy in most cases for both LR and PAoI, achieving a similar LR with only a slight 2% decrease in throughput with respect to the case where an independent channel is allocated to each user. The latter solution leads to the upper bound in performance but requires double the amount of resources than the considered OMA and NOMA schemes. However, there are extreme cases where OMA achieves a slightly greater throughput than NOMA at the expense of an increased PAoI.

We determine the energy storage needed to achieve self sufficiency to a given reliability as a function of excess capacity in a combined solar-energy generation and storage system. Based on 40 years of solar-energy data for the St. Louis region, we formulate a statistical model that we use to generate synthetic insolation data over millions of years. We use these data to monitor the energy depletion in the storage system near the winter solstice. From this information, we develop explicit formulas for the required storage and the nature of cost-optimized system configurations as a function of reliability and the excess generation capacity. Minimizing the cost of the combined generation and storage system gives the optimal mix of these two constituents. For an annual failure rate of less than 3%, it is sufficient to have a solar generation capacity that slightly exceeds the daily electrical load at the winter solstice, together with a few days of storage.

Abstract Adoptive T-cell transfer (ACT) offers a curative therapeutic option for subsets of melanoma and hematological cancer patients. To increase response rates and broaden the applicability of ACT, it is necessary to improve the post-infusion performance of the transferred T cells. The design of improved treatment strategies includes transfer of cells with a less differentiated phenotype. Such T cell subsets have high proliferative potential but require stimulatory signals in vivo to differentiate into tumor-reactive effector T cells. Thus, combination strategies are needed to support the therapeutic implementation of less differentiated T cells. Here we show that systemic delivery of tumor-associated antigens (TAAs) facilitates in vivo priming and expansion of previously non-activated T cells and enhance the cytotoxicity of activated T cells. To achieve this in vivo priming, we use flexible delivery vehicles of TAAs and a TLR7/8 agonist. Contrasting subcutaneous delivery systems, these vehicles accumulate TAAs in the spleen, thereby achieving close proximity to both cross-presenting dendritic cells and transferred T cells, resulting in robust T-cell expansion and anti-tumor reactivity. This TAA delivery platform offers a strategy to safely potentiate the post-infusion performance of T cells using low doses of antigen and TLR7/8 agonist, and thereby enhance the effect of ACT.

Kostrikov et al. report a deficiency of transcardial perfusion in brain tumor vasculature, which leads to exaggeration of drug extravasation measurements. They then demonstrate how optical tissue clearing can help to overcome this limitation and provide two machine learning-based image analysis workflows enabling detailed quantitative characterization of compound extravasation patterns as well as tumor angioarchitecture in large three-dimensional datasets.

Abstract Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P

Abstract The northern hemisphere experienced an abrupt cold event ~ 8200 years ago (the 8.2 ka event) that was triggered by the release of meltwater into the Labrador Sea, and resulting in a weakening of the poleward oceanic heat transport. Although this event has been considered a possible analogue for future ocean circulation changes due to the projected Greenland Ice Sheet (GIS) melting, large uncertainties in the amount and rate of freshwater released during the 8.2 ka event make such a comparison difficult. In this study, we compare sea surface temperatures and oxygen isotope ratios from 28 isotope-enabled model simulations with 35 paleoproxy records to constrain the meltwater released during the 8.2 ka event. Our results suggest that a combination of 5.3 m of meltwater in sea level rise equivalent (SLR) released over a thousand years, with a short intensification over ~ 130 years (an additional 2.2 m of equivalent SLR) due to routing of the Canadian river discharge, best reproduces the proxy anomalies. Our estimate is of the same order of magnitude as projected future GIS melting rates under the high emission scenario RCP8.5.

There is a trend in the automotive producers to require that foundries use more secondary aluminum alloy ingots to reduce the CO2 footprint of car production. The merits of this trend have been investigated in this study. Results have shown that requiring the use of more secondary ingots while simultaneously reducing the elongation requirement of aluminum alloy die castings is counterproductive, i.e., increases the CO2 footprint of the car over its useful life by not taking advantage of the weight reduction possible. It is recommended that (i) foundries improve their melt handling capabilities to reduce and minimize the entrainment damage made to the melt in the melting and casting process chain, and (ii) automobile producers reduce the weight of die castings by increasing requirements on elongation, to secure a reduced CO2-footprint in the designs, materials usage and life-cycle of cars.

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabol ic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integra ted beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effec t were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in thes e cohorts.

The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

A study of the first genomes of the marine Hikarchaeia, the closest known relatives of Haloarchaea, is presented. Their inclusion in ancestral reconstructions unveils an intermediate stage in the evolutionary transition from ancestral anaerobic methanogens to modern day aerobic halophiles.

Acute pulmonary embolism (PE) is a common emergency with a high morbidity and mortality. Most clinical presentations are non-specific and there is a lack of suitable biomarkers for PE. For example, the traditional D-dimer tests shows a rather high sensitivity for PE, but yet a rather low positive predictive value due to its lack of specificity. Research on novel biomarkers for PE is thus of interest to improve early diagnostics and reduce the number of unnecessary computed tomography pulmonary angiogram (CTPA) scans performed. In this study we evaluate the feasibility to use label-free quantitative proteomics to discover potential biomarkers for acute PE and to monitor changes in proteins levels in PE patients over time. Blood was collected from 8 patients with CTPA verified PE and from 8 patients presenting with same symptoms but with a negative CTPA. The samples were analyzed by liquid chromatography-mass spectrometry and thirteen protein concentrations were found to be significantly changed in PE patients compared to the CTPA negative controls. This exploratory study shows that proteomic analysis can be used to identify potential biomarkers for PE as well as to monitor changes of protein levels over time. The complement proteins play a part in PE but further studies are needed to clarify their specific role in the pathophysiological process and to look for more specific proteins.

In the United States, a public debate remains about the existence and effects of anthropogenic climate change. This skepticism is present in the agricultural sector, rendering climate science communication challenging. Due to the polarization of climate change issues and the concurrent need for agricultural adaptation, we sought to examine how scientists communicate in this sector. A survey, administered to climate scientists and pertinent U.S. federal agency staff (response rate = 43%), was conducted to examine perspectives on communicating with five agricultural stakeholder groups: agribusinesses, crop advisors, general public, producers, and policymakers. We focused on three aspects of the communication process with these stakeholders to evaluate if scientists, as messengers, were following best practices-communicator training, knowledge of stakeholder, and terminology use. We found scientists valued communication training; however, the majority had not attended formal training. Scientists had different views on climate change than producers and crop advisors but understood their perspective and were deliberate with their communication with different audiences. This suggests stakeholder knowledge and terminology use do not hinder communication between scientist and stakeholder. We also highlight three communication challenges present across stakeholder groups-stakeholder knowledge, timescale, and scientific uncertainty-and others that were specific to each stakeholder group. Future research should support scientists by identifying and resolving barriers to training and effective communication strategies for each stakeholder group that addresses these challenges.

Semi-solid aluminium alloy processing (SSM) has advanced into a more mature process with many applications. The current paper aims to investigate the in-process behaviour of a production slurry using an engineering approach to estimate the properties. A method to assess the rheological properties of a semi-solid metal slurry was tested and found capable of producing meaningful measurements. The foundations of this were to use a Rushton turbine setup for the assessment through a model to optimize the factors included in the slurry rheology. In the analysis of the static and dynamic part of the viscosity, it was concluded that the slurry turns increasingly into a solid with increasing solid fractions where the static shear strength dominates the rheology more and more compared to the dynamic components. The static yield strength was also found significantly more dominant with increasing solid fraction, suggesting that the industrial-scale analysis using models based on Ostwald–de Waale and Carreau modelling is far from sufficient for a process, such as the RheoMetal process, with a very rapid slurry generation.

Four-point bending fatigue tests were performed on semi-solid Al–7Si–Mg castings with varying magnesium contents and heat treatment conditions. Additionally, the effect of anodising on the fatigue resistance of semi-solid Al–7Si–Mg castings was evaluated. Fracture surface and microstructure analysis showed that fatigue crack initiation occurred mainly at the periphery of regions of positive macrosegregation at the casting surface, resulting most likely from exudation. The microstructure of these macrosegregation regions was mostly eutectic and was frequently found surrounded by a layer of oxides. This layer of oxides promoted weak bonding between the macrosegregation region and the surrounding material and acted as a crack initiation site. In this study, primary α-Al globule agglomerates at the casting surface and surrounded by a layer of oxides also promoted fatigue crack initiation. Fatigue resistance of semi-solid Al–7Si–Mg castings in the T5 and T6 conditions increased with the increase in the magnesium content of the alloy from 0.3 to 0.45 wt.% due to the higher precipitation hardening response. However, the increase in the magnesium content from 0.45 to 0.6 wt.% resulted in a slight decrease in the fatigue resistance. The oxide layer formed during anodising had no significant effect on the fatigue resistance of the semi-solid Al–7Si–Mg castings in this study due to the dominant effect of the macrosegregation regions on fatigue crack initiation.

FLASH radiotherapy has emerged as a treatment technique with great potential to increase the differential effect between normal tissue toxicity and tumor response compared to conventional radiotherapy. To evaluate the feasibility of FLASH radiotherapy in a relevant clinical setting, we have commenced a feasibility and safety study of FLASH radiotherapy in canine cancer patients with spontaneous superficial solid tumors or microscopic residual disease, using the electron beam of our modified clinical linear accelerator. The setup for FLASH radiotherapy was established using a short electron applicator with a nominal source-to-surface distance of 70 cm and custom-made Cerrobend blocks for collimation. The beam was characterized by measuring dose profiles and depth dose curves for various field sizes. Ten canine cancer patients were included in this initial study; seven patients with nine solid superficial tumors and three patients with microscopic disease. The administered dose ranged from 15 to 35 Gy. To ensure correct delivery of the prescribed dose, film measurements were performed prior to and during treatment, and a Farmer-type ion-chamber was used for monitoring. Treatments were found to be feasible, with partial response, complete response or stable disease recorded in 11/13 irradiated tumors. Adverse events observed at follow-up ranging from 3-6 months were mild and consisted of local alopecia, leukotricia, dry desquamation, mild erythema or swelling. One patient receiving a 35 Gy dose to the nasal planum, had a grade 3 skin adverse event. Dosimetric procedures, safety and an efficient clincal workflow for FLASH radiotherapy was established. The experience from this initial study will be used as a basis for a veterinary phase I/II clinical trial with more specific patient inclusion selection, and subsequently for human trials.

[This corrects the article DOI: 10.1371/journal.pone.0118261.].

A finite element analysis of a complex assembly was made. The material description used was a physically based material model with dislocation density as an internal state variable. This analysis showed the importance of the materials’ behavior in the process as there is discrepancy between the bolt head contact pressure and the internals state of the materials where the assembly process allows for recovery. The end state is governed by both the tightening process and the thermal history and strongly influenced by the thermal expansion of the AZ91D alloy.

ABSTRACT Streptococcus pneumoniae, a major cause of pneumonia, sepsis, and meningitis worldwide, has the nasopharynges of small children as its main ecological niche. Depletion of pneumococci from this niche would reduce the disease burden and could be achieved using small molecules with narrow-spectrum antibacterial activity. We identified the alkylated dicyclohexyl carboxylic acid 2CCA-1 as a potent inducer of autolysin-mediated lysis of S. pneumoniae, while having low activity against Staphylococcus aureus. 2CCA-1-resistant strains were found to have inactivating mutations in fakB3, known to be required for uptake of host polyunsaturated fatty acids, as well as through inactivation of the transcriptional regulator gene fabT, vital for endogenous, de novo fatty acid synthesis regulation. Structure activity relationship exploration revealed that, besides the central dicyclohexyl group, the fatty acid-like structural features of 2CCA-1 were essential for its activity. The lysis-inducing activity of 2CCA-1 was considerably more potent than that of free fatty acids and required growing bacteria, suggesting that 2CCA-1 needs to be metabolized to exert its antimicrobial activity. Total lipid analysis of 2CCA-1 treated bacteria identified unique masses that were modeled to 2CCA-1 containing lysophosphatidic and phosphatidic acid in wild-type but not in fakB3 mutant bacteria. This suggests that 2CCA-1 is metabolized as a fatty acid via FakB3 and utilized as a phospholipid building block, leading to accumulation of toxic phospholipid species. Analysis of FabT-mediated fakB3 expression elucidates how the pneumococcus could ensure membrane homeostasis and concurrent economic use of host-derived fatty acids. IMPORTANCE Fatty acid biosynthesis is an attractive antibiotic target, as it affects the supply of membrane phospholipid building blocks. In Streptococcus pneumoniae, it is not sufficient to target only the endogenous fatty acid synthesis machinery, as uptake of host fatty acids may bypass this inhibition. Here, we describe a small-molecule compound, 2CCA-1, with potent bactericidal activity that upon interactions with the fatty acid binding protein FakB3, which is present in a limited number of Gram-positive species, becomes metabolized and incorporated as a toxic phospholipid species. Resistance to 2CCA-1 developed specifically in fakB3 and the regulatory gene fabT. These mutants reveal a regulatory connection between the extracellular polyunsaturated fatty acid metabolism and endogenous fatty acid synthesis in S. pneumoniae, which could ensure balance between efficient scavenging of host polyunsaturated fatty acids and membrane homeostasis. The data might be useful in the identification of narrow-spectrum treatment strategies to selectively target members of the Lactobacillales such as S. pneumoniae.

Metal casting is an industrially important manufacturing process offering a superior combination of design flexibility, productivity and cost-effectiveness, but has limitations due to filling related defects. Several semisolid casting processes are available capable of casting at a range of solid fractions to overcome this. The current communication aims to review the filling front behaviour and give a new perspective to the gate design in semisolid processing compared to conventional high-pressure die-casting. It is shown that solid fraction and gate widths are critical to avoid instability and spraying.

Road transport and the associated fuel consumption plays a primary role in emissions. Weight reduction is critical to reaching the targeted reduction of 34% in 2025. Weight reduction in moving parts, such as pistons and brake disc rotors, provide a high-impact route to achieve this goal. The current study aims to investigate the formability of Al–Si alloys reinforced with different fractions and different sizes of SiCp to create an efficient and lightweight Al-MMC brake disk. Lanthanum (La) and cerium (Ce) were added to strengthen the aluminium matrix alloy and to improve the capability of the Al-MMC brake discs to withstand elevated temperature conditions, such as more extended braking periods. La and Ce formed intermetallic phases that further strengthened the composite. The analysis showed the processability and thermal stability of the different material’s combinations: increased particle sizes and broader size range mixture supported the formation of the SiCp particle interactions, acting as an internal scaffolding. In conclusion, the additions of Ce and La strengthened the softer matrix regions and resulted in a doubled compression peak strength of the material without affecting the formability, as demonstrated by the processing maps.

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p

Phenotyping of immune cell subsets in clinical trials is limited to well-defined phenotypes, due to technological limitations of reporting flow cytometry multi-dimensional phenotyping data. We developed a multi-dimensional phenotyping analysis tool and applied it to detect nitric oxide (NO) levels in peripheral blood immune cells before and after adjuvant ipilimumab co-administration with a peptide vaccine in melanoma patients. We analyzed inhibitory and stimulatory markers for immune cell phenotypes that were felt to be important in the NO analysis. The pipeline allows visualization of immune cell phenotypes without knowledge of clustering techniques and to categorize cells by association with relapse-free survival (RFS). Using this analysis, we uncovered the potential for a dichotomous role of NO as a pro- and anti-melanoma factor. NO was found in subsets of immune-suppressor cells associated with shorter-term (≤ 1 year) RFS, whereas NO was also present in immune-stimulatory effector cells obtained from patients with significant longer-term (> 1 year) RFS. These studies provide insights into the cell-specific immunomodulatory role of NO. The methods presented herein can be applied to monitor the pro- and anti-tumor effects of a variety of immune-based therapeutics in cancer patients.Clinical Trial Registration Number: NCT00084656 (https://clinicaltrials.gov/ct2/show/NCT00084656).

The current study investigated the relationship between the process settings and in-die conditions to understand the transitions between the different filling stages and the final pressure settings in indirect squeeze casting. A pressure sensor was placed in the die cavity to indirectly measure the evolution of pressure over time and monitor the filling process to study the in-die conditions. The pressure–time profile was analysed, and the maximum pressure and acceleration of the pressure were investigated empirically. The main conclusion of this paper is that the use of increasing intensification pressures is positive for the casting soundness. However, it must be stressed that there is a strong effect from the intensification pressure on the acceleration that has a far more reaching influence than the actual speed setting. A direct practical outcome is that a high intensification pressure has a more substantial effect than the second stage fill speed. This translates directly to a possibility of reducing the second stage fill speed to stabilise the fill front. Furthermore, this also pinpoints the need for improvements in hydraulics system designs to decouple the intensification pressure from the filling piston motion control.

A low-temperature spray deposition synthesis was developed to prepare locally hexagonally ordered mesoporous titania films with polycrystalline anatase pore walls in an evaporation-induced self-assembly process. The titania film preparation procedure is conducted completely at temperatures below 50 °C. The effects of spray time, film thickness, synthesis time prior to spray deposition, and aging time at high relative humidity after deposition on the atomic arrangement and the mesoorder of the mesoporous titania were studied. We find the crystallite size to depend on both the synthesis time and aging time of the films, where longer times result in larger crystallites. Using the photocatalytic activity of titania, the structure-directing agent is removed with UV radiation at 43–46 °C. The capability of the prepared films to remove the polymer template increased with longer synthesis and aging times due to the increased crystallinity, which increases the photocatalytic efficiency of the titania films. However, with increasingly longer times, the crystallites grow too large for the mesoorder of the pores to be maintained. This work shows that a scalable spray coating method can be used to prepare locally ordered mesoporous polycrystalline titania films by judiciously tuning the synthesis parameters.

The outlet glaciers that comprise the Northeast Greenland Ice Stream (NEGIS) have experienced accelerated retreat in recent years, yet their longterm stability remains unclear. Here, via cosmogenic surface exposure and radiocarbon ages, the authors investigate the stability of the NEGIS for the past 45 kyr.