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Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and are considered a diabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of resistance toward glucagon's effects on amino acid metabolism, resulting in an amino acid-induced hyperglucagonemia. We investigated the presence of hyperglucagonemia in individuals with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD), and whether body mass index (BMI), T2D, hepatic steatosis, and/or fibrosis contribute to this relationship. To dissect potential mechanisms, we also determined hepatic gene expression related to amino acid transport and catabolism. Individuals with MASLD had hyperglucagonemia {controls (n = 74) vs. MASLD (n = 106); median [Q1, Q3]; 4 [3, 7] vs. 8 [6, 13] pM), P < 0.0001} and were glucagon resistant (assessed by the glucagon-alanine index) {1.3 [0.9, 2.1] vs. 3.3 [2.1, 5.3] pM·mM, P < 0.0001}. These changes were associated with hepatic steatosis (P < 0.001, R2 > 0.25) independently of BMI, sex, age, and T2D. Plasma levels of glucagon were similar in individuals with MASLD when stratified on T2D status {MASLD-T2D (n = 52) vs. MASLD + T2D (n = 54); 8 [6, 11] vs. 8 [6, 13] pM, P = 0.34} and hepatic fibrosis {MASLD + F0 (n = 25) vs. MASLD + F1-F3 (n = 67); 8.4 [7.0, 13.3] vs. 7.9 [5.2, 11.6] pM, P = 0.43}. Obesity (BMI = 30 kg/m2) did not alter glucagon levels (P = 0.65) within groups (control/MASLD). The mRNA expression of proteins involved in amino acid transport and catabolism was downregulated in MASLD. Thus, relative hyperglucagonemia is present in individuals with biopsy-verified MASLD, and hepatic steatosis partially drives hyperglucagonemia and glucagon resistance, irrespective of T2D, BMI, and hepatic fibrosis. NEW & NOTEWORTHY: Individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) present with increased plasma levels of glucagon (hyperglucagonemia), irrespective of body mass index (BMI) and type 2 diabetes. Therefore, MASLD and the resultant hyperglucagonemia may act as a diabetogenic risk factor. Notably, hepatic steatosis was a significant contributor to the hyperglucagonemia in MASLD, potentially unveiling a pathway for the hyperglucagonemia in some patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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. Intranasal immunization with capsular pneumococcal polysaccharides 12F and iNKT agonist α-galactosylceramide in cationic liposomes protects mice from S. pneumoniae 12F infection. [ABSTRACT FROM AUTHOR]

As part of the southern Cascades, Mt. Hood is the tallest and most glacierized peak in Oregon, USA. Despite alpine glaciers being one the clearest indicators of human-caused climate change, the 21st century behavior of glaciers on Mt. Hood has not been directly documented at the ground level. Here we directly measure changes in the extents of Mt. Hood's glaciers from 2003 to 2023 and find dramatic retreat of all glaciers, with one glacier ceasing to flow (joining another glacier that ceased flowing before 2003) and another three glaciers retreating towards this status. By 2023, Mt. Hood glaciers had lost ∼17 % of their 2015–2016 area and ∼39 % of their 1981 area. The rate of area loss from 2015–2016 to 2023 (∼2.10 % yr -1) was ∼2.6 times faster than the rate from 1981 to 2015–2016 (∼0.81 % yr -1). The seven largest glaciers on the volcano lost ∼25 % of their area between 2000 and 2023. Comparison to historic records of glacier area back to 1907 shows that this 21st century retreat is unprecedented relative to the previous century. The rate of area loss over the last 23 years (∼1.07 % yr -1) was ∼1.9 times faster than the fastest rate documented in the last century from 1907 to 1946 (∼0.56 % yr -1) and ∼3.5 times faster than the 20th century average (∼0.31 % yr -1). This unprecedented rate of retreat corresponds to regional summer warmth reaching 1.7–1.8 °C (2013–2023 average) relative to the early 1900s, but not with regional changes in winter precipitation. We conclude that Mt. Hood's glaciers are retreating in response to a warming climate and that this recession has accelerated in the 21st century. [ABSTRACT FROM AUTHOR]

At the end of August 1941, the Nazi German Einsatzgruppe , together with German Police Battalion 320 and Ukrainian auxiliaries, killed approximately 23,600 persons (mainly Jews) at Kamianets-Podilskyi. While some researchers assert that Roma were deported from Hungary and Hungarian-occupied Transcarpathia (present-day Ukraine) despite the absence of official reports, other scholars argue that Hungarian leaders may have planned to ethnically "cleanse" the area of Roma, but the plan was never executed, resulting in no deportations or deaths. This article presents new findings that support the former position, and argues that roughly one thousand Roma were expelled from Transcarpathia. New evidence includes a report detailing the ongoing operation to expel Roma, census data indicating a significant reduction in the Roma population near the border, as well as indications that individuals other than Jews were expelled, likely Roma. Only circumstantial evidence—verbal orders to eliminate Roma and reports of Roma killings by the same special commando in different locations—supports the claim that Roma were killed in the August 1941 massacre, though later reports from 1942 explicitly identify Roma victims. After analyzing this new evidence, the author supports the claim that Roma were deported and potentially killed earlier than had previously been known. [ABSTRACT FROM AUTHOR]

Increased recycling of plastics is an essential step toward a more sustainable use of materials, where some of the most challenging fractions are engineering materials and composites. Used pump houses prepared from glass fiber (GF)‐reinforced blends of polyphenylene oxide (PPO) and high‐impact polystyrene (HIPS) obtained through a take‐back scheme (take‐back, TB) were characterized and shredded for use in the preparation of new composites by injection molding. Initial degradation was observed on the surface of the TB parts; however, the core of the material was unaffected. Mechanical reprocessing of regrind and virgin material showed a reduction of tensile strength already at 10% regrind, which was attributed to fiber length reduction during reprocessing. At the same time, Young's modulus and extension at break were largely unaffected, confirming that 25% of TB could be included without any additional loss of properties. As a worst‐case scenario, tests with extensively degraded material showed that Young's modulus and tensile strength would ultimately be reduced with an increasing amount of heavily degraded material and that a balance would have to be found between loss of properties and recycled content for heavily degraded material. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease. NEW & NOTEWORTHY: Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: Hydroxyurea (HU) is a commonly used first‐line treatment in patients with polycythemia vera (PV). However, approximately 15%–24% of PV patients report intolerance and resistance to HU. Methods: This phase IV, European, real‐world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24‐month follow‐up. The primary objective was to describe the profile and disease burden of PV patients. Results: In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment‐related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug‐related. Conclusion: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated. [ABSTRACT FROM AUTHOR]

As part of the southern Cascades, Mt. Hood is the tallest and most glaciated peak in Oregon, U.S.A. Despite alpine glaciers being one the clearest indicators of human-caused climate change, the 21st century behavior of glaciers on Mt. Hood has not been directly documented. Here we directly measure changes in Mt. Hood's glacier extents from 2003 to 2023 and find dramatic retreat of all glaciers, with one glacier disappearing, another two nearing this status, and a third retreating towards this status. The seven largest glaciers on the volcano lost ~2.8 km2, or ~40 % of their area in the 21st century. Comparison to historic records of glacier area back to 1907 shows that this 21st-century retreat is unprecedented with respect to the previous century and has outpaced modeled glacier changes. The rate of retreat over the last 23 years is more than double the fastest rate documented in the last century from 1907 to 1946. We demonstrate that this century-scale retreat strongly correlates with regional 30-year-average climate warming of ~1.1 ºC since the early 1900s, but not with regional changes in precipitation. We conclude that Mt. Hood's glaciers are retreating in response to a warming climate and that this recession has accelerated in the 21st century, with attendant consequences for water resources. [ABSTRACT FROM AUTHOR]

As part of the southern Cascades, Mt. Hood is the tallest and most glaciated peak in Oregon, U.S.A. Despite alpine glaciers being one the clearest indicators of human-caused climate change, the 21st century behavior of glaciers on Mt. Hood has not been directly documented. Here we directly measure changes in Mt. Hood's glacier extents from 2003 to 2023 and find dramatic retreat of all glaciers, with one glacier disappearing, another two nearing this status, and a third retreating towards this status. The seven largest glaciers on the volcano lost ~2.8 km², or ~40% of their area in the 21st century. Comparison to historic records of glacier area back to 1907 shows that this 21st-century retreat is unprecedented with respect to the previous century and has outpaced modeled glacier changes. The rate of retreat over the last 23 years is more than double the fastest rate documented in the last century from 1907 to 1946. We demonstrate that this century-scale retreat strongly correlates with regional 30-year-average climate warming of ~1.1°C since the early 1900s, but not with regional changes in precipitation. We conclude that Mt. Hood's glaciers are retreating in response to a warming climate and that this recession has accelerated in the 21st century, with attendant consequences for water resources. [ABSTRACT FROM AUTHOR]

A critical milestone to the adoption of 3D tow reinforced hybrid-molded structures is the development of design guidelines and analysis techniques for accurate performance modelling. The cross-sectional dimensions of the tow bundle leads to fiber length discrepancies between the inner fibers and the outer fibers which manifest as tow spreading and local fiber waviness. The effects of simulating the resulting fiber orientations and effective elastic properties is investigated by modelling a representative beam in tension and bending load cases and comparing to previous experimental results. Accounting for fiber waviness in tension demonstrated greatly improved part stiffness predictions. Spread tow bundles improved predicted strength and stiffness over simulations where tow was constrained to a uniform cross section. Increased tow reinforcement increased bending stiffness, but failure behavior was significantly influenced by the overmolding material. [ABSTRACT FROM AUTHOR]

Objective: The effect of oral glucose-induced release of gastrointestinal hormones on satiety and appetite independently of prevailing plasma glucose excursions is unknown. The objective is to investigate the effect of oral glucose on appetite and satiety sensations as compared to isoglycemic IV glucose infusion (IIGI) in healthy volunteers. Design: A crossover study involving two study days for each participant. Participants: Nineteen healthy participants (6 women, mean age 55.1 [SD 14.2] years; mean body mass index 26.7 [SD 2.2] kg/m²). Interventions: Each participant underwent a 3-h 50-g oral glucose tolerance test (OGTT) and, on a subsequent study day, an IIGI mimicking the glucose excursions from the OGTT. On both study days, appetite and satiety were indicated regularly on visual analog scale (VAS), and blood was drawn regularly for measurement of pancreatic and gut hormones. Primary outcomes: Difference in appetite and satiety sensations during OGTT and IIGI. Results: Circulating concentrations of glucose-dependent insulinotropic polypeptide (P < .0001), glucagon-like peptide 1 (P < .0001), insulin (P < .0001), C-peptide (P < .0001), and neurotensin (P = .003) increased significantly during the OGTT as compared to the IIGI, whereas glucagon responses were similarly suppressed (P = .991). Visual analog scale-assessed ratings of hunger, satiety, fullness, thirst, well-being, and nausea, respectively, were similar during OGTT and IIGI whether assessed as mean 0-3-h values or area under the curves. For both groups, a similar, slow increase in appetite and decrease in satiation were observed. Area under the curve, for prospective food consumption (P = .049) and overall appetite score (P = .044) were slightly lower during OGTT compared to IIGI, whereas mean 0-3-h values were statistically similar for prospective food consumption (P = .053) and overall appetite score (P = .063). Conclusions: Despite eliciting robust responses of appetite-reducing and/or satiety-promoting gut hormones, we found that oral glucose administration has little or no effect on appetite and satiety as compared to an IIGI, not affecting the release of appetite-modulating hormones. Trial registry no: ClinicalTrials.gov: NCT01492283 and NCT06064084. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The addition of polyetheretherketone (PEEK) filler to polytetrafluoroethylene (PTFE) is known to result in an orders-of-magnitude decrease in dry sliding wear of PTFE. Unlike similar ultra-low wear PTFE composites, PEEK as a filler is particularly effective since ultra-low wear of PEEK–PTFE is insensitive to environmental moisture. Mechanisms of low wear in PEEK–PTFE, i.e., formation of tenacious transfer films is hypothesized to occur independent of tribochemically generated functional groups, relying instead on intrinsic polar sites within the PEEK polymer chain. The present study aims to probe whether tribochemistry-independent mechanisms of low wear in PEEK–PTFE operate when sliding against substrates with different material chemistries. Specifically, we test the hypothesis that PEEK–PTFE composites are able to sustain low wear against a range of counterface materials, in particular non-ferrous alloys, through tribochemistry-independent mechanisms similar to those which operate under low moisture environments. Results of this work show that wear rate against steel, brass and aluminum alloys vary between 10−7 and 10−6 mm3/Nm, driven largely by the properties (coverage, thickness and roughness) of resulting transfer films. Interestingly, spectroscopic analyses of interfacial films reveal no significant differences after sliding on the different substrates, which suggest that mechanisms of low wear operate independent of the choice of counterface material. [ABSTRACT FROM AUTHOR]

Objective: To estimate the cumulative incidences of orofacial conditions related to temporomandibular joint (TMJ) juvenile idiopathic arthritis (JIA) between diagnosis in childhood to transition into adult care, and to identify features in JIA associated with TMJ involvement. Methods: A population‐based cohort analysis was conducted of patients with JIA involving longitudinal data on orofacial health from 2000 to 2018. Regardless of TMJ status, the patients were referred to the Regional Specialist Craniofacial Clinic of Western Denmark for routine orofacial examinations. Data collection included information about disease‐specific background characteristics, TMJ involvement, JIA‐induced dentofacial deformity, and orofacial symptoms and dysfunction. Results: A total of 613 patients were followed up with a mean clinical TMJ observation time of 4.0 years. From JIA onset to transition into adult care, the cumulative incidence of patients with JIA involvement of the TMJ was 30.1%. Furthermore, 20.6% of the cohort had developed arthritis‐induced dentofacial deformity. A substantial proportion of the cohort experienced several events with orofacial symptoms (23.5%) and dentofacial dysfunction (52%). Young age at diagnosis (<9 years), female gender, and antinuclear antibody positivity were significantly associated with TMJ involvement. Conclusion: Orofacial signs and symptoms were frequent findings in children and adolescents with JIA. TMJ involvement was seen in 30.1% of the cohort; and 20.6% of the total cohort developed JIA‐related dentofacial deformity before transition into adult care. This is the first population‐based study in the era of available biologic treatments to document these frequent orofacial complications in children with JIA. [ABSTRACT FROM AUTHOR]

In addition to antioxidative and anti-inflammatory properties, activators of the cytoprotective nuclear factor erythroid-2-like-2 (NRF2) signaling pathway have antiviral effects, but the underlying antiviral mechanisms are incompletely understood. We evaluated the ability of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone methyl (BARD), sulforaphane (SFN), and the inhibitor of exportin-1 (XPO1)-mediated nuclear export selinexor (SEL) to interfere with influenza virus A/Puerto Rico/8/1934 (H1N1) infection of human cells. All compounds reduced viral titers in supernatants from A549 cells and vascular endothelial cells in the order of efficacy SEL>4OI>BARD = SFN, which correlated with their ability to prevent nucleo-cytoplasmic export of viral nucleoprotein and the host cell protein p53. In contrast, intracellular levels of viral HA mRNA and nucleocapsid protein (NP) were unaffected. Knocking down mRNA encoding KEAP1 (the main inhibitor of NRF2) or inactivating the NFE2L2 gene (which encodes NRF2) revealed that physiologic NRF2 signaling restricts IAV replication. However, the antiviral effect of all compounds was NRF2-independent. Instead, XPO1 knock-down greatly reduced viral titers, and incubation of Calu3 cells with an alkynated 4OI probe demonstrated formation of a covalent complex with XPO1. Ligand–target modelling predicted covalent binding of all three NRF2 activators and SEL to the active site of XPO1 involving the critical Cys528. SEL and 4OI manifested the highest binding energies, whereby the 4-octyl tail of 4OI interacted extensively with the hydrophobic groove of XPO1, which binds nuclear export sequences on cargo proteins. Conversely, SEL as well as the three NRF2 activators were predicted to covalently bind the functionally critical Cys151 in KEAP1. Blocking XPO1-mediated nuclear export may, thus, constitute a "noncanonical" mechanism of anti-influenza activity of electrophilic NRF2 activators that can interact with similar cysteine environments at the active sites of XPO1 and KEAP1. Considering the importance of XPO1 function to a variety of pathogenic viruses, compounds that are optimized to inhibit both targets may constitute an important class of broadly active host-directed treatments that embody anti-inflammatory, cytoprotective, and antiviral properties. Author summary: Virus infections often cause organ damage via excessive inflammation and oxidative stress. The identification of host-directed treatments that reduce inflammation, accumulation of reactive oxygen species, and viral infectivity is an important goal of antiviral drug development. One advantage of host-directed antivirals is that their targets are encoded by the stable host genome, making emergence of viral resistance less likely. The KEAP1/NRF2 signaling pathway is the most important pathway in humans that protects cells from oxidative stress, and it also induces antiviral and anti-inflammatory responses. NRF2 activators, therefore, are promising candidates for development of host-directed antivirals. We evaluated three NRF2-activating compounds as host-directed treatments for influenza A virus (IAV) infection. All three compounds reduced viral replication, cellular inflammation, and reactive oxygen species. Surprisingly, these effects were completely independent of NRF2 signaling. Instead, we found that these compounds (particularly 4-octyl itaconate) interfere with export of viral RNA/protein complexes from the nucleus, thereby reducing release of viral particles. The most plausible explanation is that the "natural" target of these compounds, KEAP1 (which limits NRF2 signaling), and the nuclear export factor XPO1 (which is required for egress of IAV from the nucleus) contain similar binding sites, thus allowing "NRF2 activators" to also inhibit XPO1. [ABSTRACT FROM AUTHOR]

To comprehensively understand the saturation of two-dimensional (2D) magnetized Kelvin–Helmholtz-instability-driven turbulence, energy transfer analysis is extended from the traditional interaction between scales to include eigenmode interactions, by using the nonlinear couplings of linear eigenmodes of the ideal instability. While both kinetic and magnetic energies cascade to small scales, a significant fraction of turbulent energy deposited by unstable modes in the fluctuation spectrum is shown to be re-routed to the conjugate-stable modes at the instability scale. They remove energy from the forward cascade at its inception. The remaining cascading energy flux is shown to attenuate exponentially at a small scale, dictated by the large-scale stable modes. Guided by a widely used instability-saturation assumption, a general quasi-linear model of instability is tested by retaining all nonlinear interactions except those that couple to the large-scale stable modes. These complex interactions are analytically removed from the magnetohydrodynamic equations using a novel technique. Observations are an explosive large-scale vortex separation instead of the well-known merger of 2D, a dramatic enhancement in turbulence level and spectral energy fluxes, and a reduced small-scale dissipation length scale. These show the critical role of the stable modes in instability saturation. Possible reduced-order turbulence models are proposed for fusion and astrophysical plasmas, based on eigenmode-expanded energy transfer analyses. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to perform a systematic review, meta-analysis and cost-consequence analysis of the single-use bronchoscope, Ambu aScopeTM 5 Broncho, in relation to reusable flexible bronchoscopes (RFB) available within three high procedure volume university hospitals and academic institutions in the USA. Methods: The primary outcome was incremental cost and the secondary outcome was incremental cross-infection risk of use for both the single-use flexible bronchoscope (SUFB) and RFBs. Cost estimates included capital, repair, and reprocessing costs derived from a prospective observational micro-costing approach within three large university hospitals and academic institutions. All costs were valued in 2022 US dollars (USD). A meta-analysis based on literature covering cross-contamination and infection from 2010 to 2020 investigated cross-infection risk following bronchoscopy procedures with RFBs. Capital costs were discounted at 3% over 5–8 years. All parameters were evaluated using both univariate deterministic and probabilistic sensitivity analyses. Results: In high-volume hospitals, RFBs were cost minimizing compared to SUFBs. Probabilistic sensitivity analysis showed that RFBs were cost saving in 88% of iterations. Univariate analyses illustrated sensitivity of the base-case result to the procedure volume. Data from sensitivity analyses suggest that the two interventions are cost neutral at a break-even point of 756 procedures per year or 46 procedures per bronchoscope per year. Conclusion: Assuming equivalent clinical performance, single-use flexible bronchoscopes are not cost minimizing when including the costs associated with cross-infection in high-volume US university hospitals and academic institutions. Overall, the benefits of conversion from RFBs to SUFBs are dependent on the annual procedure volume of individual hospitals, expected cross-infection risk, and purchase price of the aScope 5 Broncho. [ABSTRACT FROM AUTHOR]

Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3‐membered N‐heterocyclic compounds—such as aziridines, azirines, and oxaziridines—possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α‐lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α‐lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo‐ and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α‐lactam‐based electrophilic probes in covalent chemical biology. [ABSTRACT FROM AUTHOR]

Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3‐membered N‐heterocyclic compounds—such as aziridines, azirines, and oxaziridines—possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α‐lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α‐lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo‐ and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α‐lactam‐based electrophilic probes in covalent chemical biology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The effectiveness of rotary degassing on the defect formation and mechanical properties of the final casting of aluminium alloy EN AC 46000 was investigated, along with its impact on the energy consumption in the casting furnace. In the melt preparation prior to casting, the molten metal is usually transported from the melting furnace to the casting furnace with rotary degassing as a cleaning procedure. Under the conditions of this specific study, negligible degradation was observed in the mechanical properties of the final cast component in an aluminium EN AC 46000 alloy after removing the rotary degassing step in the process. Furthermore, removing the rotary degassing step led to a reduced temperature drop in the melt, thus minimizing the need for reheating (energy consumption) by up to 75% in the casting furnace. The reduced energy consumption was up to 124,000 kWh in yearly production in a 1500 kg casting furnace. The environmental impact showed a ~1500 kg reduction in CO2 for one 1500 kg electrical casting furnace in a year. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The finite element three-dimensional transient model of the annealing process, including conductive and convective heat transfer in an aluminum (Al) coil was developed, implemented, and validated. It combines winding force dependent effective radial thermal conductivity model and the novel convective heat transfer modeling methodology. Experimental validation of the finite element model was performed for two industrial coils having different dimensions, strip thickness and crowning depth. The general agreement between the predicted and measured temperatures for most of the probes was better than 10% at the target material temperature. A series of measurements were configured and performed to supply both the input and validation data for the simulations. The effect of the additional wetted area on the convective heat transfer at the coil base was quantified. The guidelines on the virtual prototyping of the Al coil annealing process were provided, which can be of interest for the process designers. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Glass fiber (GF) composites are one of the significant challenges in recycling thermoset materials. After pyrolysis, the glass fibers lack sufficient strength and show poor matrix compatibility. Here we have investigated a series of multifunctional silane and silazane agents for surface modification of recycled glass fibers that provide a combination of hydrophobic properties and residual reactive groups on the surface. This allowed testing of interfacial effects from the surface modification as well as a potential synergistic compatibilization using maleated PP (MAPP). The treated GFs were used to prepare new polypropylene (PP) composites by multiple extrusion steps, resulting in a series of composites where the dispersion efficiency was attributed mainly to the surface chemistry and compatibilization effects. The amino‐silane modifications of the recycled fibers resulted in further improvements in the mechanical properties of the PP composites in comparison with the hydrophobized GFs. Moreover, synergistic effects from the addition of MAPP were observed with scanning electron microscopy. The results clearly demonstrate that the surface modifications were effective and good alternatives to currently used methods. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background/Aim: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusionpositive solid tumors. Patient and Methods: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. Results: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. Conclusion: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse. [ABSTRACT FROM AUTHOR]

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens. [ABSTRACT FROM AUTHOR]

Silicones are typically cured at room temperature by means of metal catalyst such as tin or platinum. When networks are formed, the catalyst becomes unrecoverable, which is of economic as well as environmental concern. Very few methods for producing metal catalyst‐free room‐temperature‐vulcanized (RTV) silicones exist and require conditions unavailable in industrial settings. Through the study of organic polysilazane (PSz) reactivity with simple alcohols by nuclear magnetic resonance, an unexpected fragmentation preference is discovered for breaking the SiN bond rather than the SiH; thereby, casting a new light on the fragmentation mechanism of PSzs. Utilizing the PSz fragmentation as a silyl ether coupling agent for multifunctional carbinol silicones, a method of producing catalyst‐free RTV silicone networks at ambient conditions is presented. These silicone networks are proven chemically similar to a standard condensation‐cured silicone and stoichiometric variations of PSz content demonstrate adjustable network properties. [ABSTRACT FROM AUTHOR]

In this study, a new tag-and-trace method of α-Al crystals was developed and used to study the dissolution of a rotating Al-3Si-0.15Ti cylinder immersed into a superheated commercial purity aluminum melt. The developed tag-and-trace method consists of tagging the primary crystals of an alloy with the microsegregation of a peritectic forming solute element, e.g., titanium in aluminum alloys. During solidification, the primary crystals form with a high concentration of the peritectic forming solute, decreasing in the adjacent growth regions of the same crystal. After solidification, the solute microsegregation tag in the interior of the primary crystals can be revealed by color etching. In this work, an Al-3Si-0.15Ti cylinder with all the primary α-Al crystals tagged with titanium was immersed into a superheated titanium-free aluminum alloy. The superheat was varied, and all samples were quenched 10s after immersion of the cylinder. The tagged α-Al crystals from the original cylinder could be distinguished from the non-tagged α-Al crystals formed in the thermally undercooled region surrounding the cylinder and during quenching. Indications of liquid penetration were observed in some α-Al crystals, which indicates that disintegration of α-Al crystals may occur during stirring of the alloy cylinder into a superheated alloy. [ABSTRACT FROM AUTHOR]

With the advent of 5G technology, the notion of latency got a prominent role in wireless connectivity, serving as a proxy term for addressing the requirements for real-time communication. As wireless systems evolve toward 6G, the ambition to immerse the digital into physical reality will increase. Besides making the real-time requirements more stringent, this immersion will bring the notions of time, simultaneity, presence, and causality to a new level of complexity. A growing body of research points out that latency is insufficient to parameterize all real-time requirements. Notably, one such requirement that received significant attention is information freshness, defined through the Age of Information (AoI) and its derivatives. In general, the metrics derived from a conventional black-box approach to communication network design are not representative of new distributed paradigms, such as sensing, learning, or distributed consensus. The objective of this article is to investigate the general notion of timing in wireless communication systems and networks, and its relation to effective information generation, processing, transmission, and reconstruction at the senders and receivers. We establish a general statistical framework of timing requirements in wireless communication systems, which subsumes both latency and AoI. The framework is made by associating a timing component with the two basic statistical operations: decision and estimation. We first use the framework to present a representative sample of the existing works that deal with timing in wireless communication. Next, it is shown how the framework can be used with different communication models of increasing complexity, starting from the basic Shannon one-way communication model and arriving at communication models for consensus, distributed learning, and inference. Overall, this article fills an important gap in the literature by providing a systematic treatment of various timing measures in wireless communication and sets the basis for design and optimization for the next-generation real-time systems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Massive random access plays a central role in supporting the Internet of Things (IoT), where a subset of a large population of users simultaneously transmit small packets to a central base station. While there has been much research on the design of protocols for massive access in the uplink, the problem of providing message acknowledgments back to the users has been somewhat neglected. Reliable communication needs to rely on two-way communication for acknowledgement and retransmission. Nevertheless, because of the many possible subsets of active users, providing acknowledgments requires a significant amount of bits. Motivated by this, we define the problem of massive ARQ (Automatic Retransmission reQuest) protocol and introduce efficient methods for joint encoding of multiple acknowledgements in the downlink. The key idea towards reducing the number of bits used for massive acknowledgments is to allow for a small fraction of false positive acknowledgments. We analyze the implications of this approach and the impact of acknowledgment errors in scenarios with massive random access. Finally, we show that these savings can lead to a significant increase in the reliability when retransmissions are allowed since it allows the acknowledgment message to be transmitted more reliably using a much lower rate. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Resource efficiency, energy usage, and carbon footprint drive the need to use aluminium alloys to manufacture lightweight components. The current paper targets the effects of alloy composition on the heat associated with remelting from a material circularity perspective. Si as an alloying element increases the required heat in the recycling cycle. Limiting the Si content in cast materials can reduce the energy needed in the recycling process by 20%, leading to significant gains in energy usage and CO2 emissions from gas heated furnaces and fossil fuel-generated electricity. [ABSTRACT FROM AUTHOR]

Background: A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection.Methods: HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization.Results: Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response.Conclusions: HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate. [ABSTRACT FROM AUTHOR]

The Clovis-first model for the peopling of the Americas by ~13.4 ka has long invoked the Ice-Free Corridor (IFC) between the retreating margins of the Cordilleran and Laurentide ice sheets as the migration route from Alaska and the Yukon down to the Great Plains. Evidence from archaeology and ancient genomics, however, now suggests that pre-Clovis migrations occurred by at least ~15.5 to 16.0 ka or earlier than most recent assessments of the age of IFC opening at ~14 to 15 ka, lending support to the use of a Pacific coast migration route instead. Uncertainties in ages from the IFC used in these assessments, however, allow for an earlier IFC opening which would be consistent with the availability of the IFC as a migration route by ~15.5 to 16.0 ka. Here, we use 64 cosmogenic (10Be) exposure ages to closely date the age of the full opening of the IFC at 13.8 ± 0.5 ka. Our results thus clearly establish that the IFC was not available for the first peopling of the Americas after the Last Glacial Maximum, whereas extensive geochronological data from the Pacific coast support its earlier availability as a coastal migration route. [ABSTRACT FROM AUTHOR]