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The steel sector currently accounts for 7% of global energy-related CO 2 emissions and requires deep reform to disconnect from fossil fuels. Here, we investigate the market competitiveness of one of the widely considered decarbonisation routes for primary steel production: green hydrogen-based direct reduction of iron ore followed by electric arc furnace steelmaking. Through analysing over 300 locations by combined use of optimisation and machine learning, we show that competitive renewables-based steel production is located nearby the tropic of Capricorn and Cancer, characterised by superior solar with supplementary onshore wind, in addition to high-quality iron ore and low steelworker wages. If coking coal prices remain high, fossil-free steel could attain competitiveness in favourable locations from 2030, further improving towards 2050. Large-scale implementation requires attention to the abundance of suitable iron ore and other resources such as land and water, technical challenges associated with direct reduction, and future supply chain configuration. Facility-level analysis of green H2- based steel production demonstrates co-location of high-quality renewables and iron ore resources is imperative for cost minimisation.

Steel is an indispensable component of our physical environment and the most consumed metal on earth at 2 billion tonnes per annum. Continuance of this consumption and production pattern is incongruent with climate change mitigation; steel production is deeply dependent on fossil fuels with the sector emitting about one-tenth of energy-related global greenhouse gas emissions. Decarbonisation must commence immediately to reach near zero-emissions by 2050 and not exceed the allocated 30-year carbon budget aligned to a 1.5°C global warming trajectory. This presents a hefty challenge given the fundamental change in energy inputs required, consequent modification of metallurgical processes, and restructuring of the supporting supply chains. Yet, a significant opportunity lies in transitioning the industrial sector towards electrification with zero-carbon electricity inputs. In terms of physical pathways to near zero-emissions, the current literature body focuses on process level improvements, whilst supply chain assessments from raw materials to markets are largely absent. The energy paradigm shift introduces multiple novel supply chain elements worth exploring, including green hydrogen and iron trade, matching variable renewables with processes of varying flexibility, and opening of green markets under carbon policies. This literature gap is addressed in this thesis through mathematical modelling and geospatial analysis at multiple scales, spanning individual processes to the complete supply chain, and applied in local, regional, and global contexts.The systems-based, locational research agenda allows exploration and evaluation of novel configurations for renewables-based steel supply chains. The technological focus is on hydrogen-based direct reduction of iron followed by the electric arc furnace, which reduces emissions to near zero and is rapidly reaching commerciality. The most significant tangible contributions of this thesis are the facility-level and supply chain optimisation models, which can be applied in any locality or region of interest. However, only through the meaningful case study analyses did critical insights emerge, of particular interest: (i) it is economically and energetically rational to reconfigure steel supply chains around high-quality renewables and iron ore deposits; (ii) co-locating hydrogen and iron production, and dislocating iron and steel production through green iron trade, introduces a valuable trade paradigm that takes advantage of upstream renewables whilst maintaining downstream market strongholds, (iii) iron ore producers have an integral part to play in the green steel transition, and a significant opportunity exists for these nations to transition from predominantly extractive to manufacturing economies, (iv) regional trade alliances and carbon policies are critical to green steel transitions, and (v) sectorial decoupling from fossil fuels requires well-timed investments and low-carbon energy system integration. Resource reallocation in the steel industry calls for supply chain restructuring; carrying over of fossil-based legacies will be a lost opportunity.

The steel industry's clean energy transition can enable new market creation and economic growth stimulation. Yet, the most efficient and feasible pathway to decouple the sector from fossil fuels remains unclear, particularly within emerging markets and unstable socio-political contexts. A new University of Oxford study by Devlin et al provides a blueprint for reconfiguring plant locations and reallocating resources through a Ukrainian case study, which captures alternative post-war conditions. Much of Ukraine's pre-war steel production capacity has been destroyed. Reconstructing Ukraine will require vast amounts of steel, which should be locally produced to stimulate the postwar recovery and economic growth. The projected domestic demand for steel, in addition to perceived export demands for green iron and steel from nearby European markets, should provide the steady demand signal required for investment. The vast destruction of Ukraine's iron and steelmaking assets represents a stark opportunity to rebuild a thriving industrial sector which is independent of fossil fuels. Ukraine is well-positioned to supply European green steel markets, which will provide employment throughout the value chain, and deliver returns to the economy well beyond the original investments.

Background Exposure to air pollution is associated with elevated cardiovascular risk. Evidence shows that omega-3 polyunsaturated fatty acids (omega-3 PUFA) may attenuate the adverse cardiovascular effects of exposure to fine particulate matter (PM 2.5 ). However, it is unclear whether habitual dietary intake of omega-3 PUFA protects against the cardiovascular effects of short-term exposure to low-level ambient air pollution in healthy participants. In the present study, sixty-two adults with low or high dietary omega-3 PUFA intake were enrolled. Blood lipids, markers of vascular inflammation, coagulation and fibrinolysis, and heart rate variability (HRV) and repolarization were repeatedly assessed in 5 sessions separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily PM 2.5 and maximum 8-h ozone (O 3 ) concentrations were obtained from nearby air quality monitoring stations. Linear mixed-effects models were used to assess the associations between air pollutant concentrations and cardiovascular responses stratified by the omega-3 intake levels. Results The average concentrations of ambient PM 2.5 and O 3 were well below the U.S. National Ambient Air Quality Standards during the study period. Significant associations between exposure to PM 2.5 and changes in total cholesterol, von Willebrand factor (vWF), tissue plasminogen activator, D-dimer, and very-low frequency HRV were observed in the low omega-3 group, but not in the high group. Similarly, O 3 -associated adverse changes in cardiovascular biomarkers (total cholesterol, high-density lipoprotein, serum amyloid A, soluable intracellular adhesion molecule 1, and vWF) were mainly observed in the low omega-3 group. Lag-time-dependent biphasic changes were observed for some biomarkers. Conclusions This study demonstrates associations between short-term exposure to PM 2.5 and O 3 , at concentrations below regulatory standard, and subclinical cardiovascular responses, and that dietary omega-3 PUFA consumption may provide protection against such cardiovascular effects in healthy adults.

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in (APDS1) or (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Tumor protein p53 ( TP53 ) is the most frequently mutated gene in cancer 1 , 2 . In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease 3 , 4 , rapid transformation to acute myeloid leukemia (AML) 5 , resistance to conventional therapies 6 – 8 and dismal outcomes 9 . Consistent with the tumor-suppressive role of TP53 , patients harbor both mono- and biallelic mutations 10 . However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53 -mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R) 11 . Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response. Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation

Background Short-term exposure to ambient nitrogen dioxide (NO 2 ) is associated with adverse respiratory and cardiovascular outcomes. Supplementation of omega-3 polyunsaturated fatty acids (PUFA) has shown protection against exposure to fine particulate matter. This study aims to investigate whether habitual omega-3 PUFA intake differentially modify the associations between respiratory and cardiovascular responses and short-term exposure to ambient NO 2 . Methods Sixty-two healthy participants were enrolled into low or high omega-3 groups based on their habitual omega-3 PUFA intake. Each participant was repeatedly assessed for lung function, blood lipids, markers of coagulation and fibrinolysis, vascular function, and heart rate variability (HRV) in up to five sessions, each separated by at least 7 days. This study was carried out in the Research Triangle area of North Carolina, USA between October 2016 and September 2019. Daily ambient NO 2 concentrations were obtained from an area air quality monitoring station on the day of outcome assessment (Lag0), 4 days prior (Lag1-4), as well as 5-day moving average (5dMA). The associations between short-term exposure to NO 2 and the measured indices were evaluated using linear mixed-effects models stratified by omega-3 levels and adjusted by covariates including relative humidity and temperature. Results The average concentration of ambient NO 2 during the study periods was 5.3±3.8 ppb which was below the National Ambient Air Quality Standards (NAAQS). In the high omega-3 group, an interquartile range (IQR) increase in short-term NO 2 concentrations was significantly associated with increased lung function [e.g. 1.2% (95%CI: 0.2%, 2.2%) in FVC at lag1, 2.6% (95%CI: 0.4%, 4.8%) in FEV1 at 5dMA], decreased blood lipids [e.g. -2.6% (95%CI: -4.4%, -0.9%) in total cholesterol at lag2, -3.1% (95%CI: -6.1%, 0.0%) in HDL at 5dMA, and -3.1% (95%CI: -5.5%, -0.7%) in LDL at lag2], improved vascular function [e.g. 8.9% (95%CI: 0.6%, 17.2%) increase in FMD and 43.1% (95%CI: -79.8%, -6.3%) decrease in endothelin-1 at 5dMA], and changed HRV parameters [e.g. -7.2% (95%CI: -13.6%, -0.8%) in HFn and 13.4% (95%CI: 0.2%, 28.3%) in LF/HF ratio at lag3]. In the low omega-3 group, an IQR increase in ambient NO 2 was associated with elevations in coagulation markers (von Willebrand Factor, D-dimer) and a decrease in HRV (very-low frequency); however, null associations were observed between short-term NO 2 exposure and changes in lung function, blood lipids, and vascular function. Conclusions The results in this study imply that dietary omega-3 PUFA consumption may offer respiratory and vascular benefits in response to short-term exposure of healthy adults to NO 2 levels below the NAAQS. Trial registration ClinicalTrials.gov ( NCT02921048 ).

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer’s disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. Graphical abstract pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.

Background Air pollution-induced changes in cardiac electrophysiological properties could be a pathway linking air pollution and cardiovascular events. The evidence of air pollution effects on the cardiac conduction system is incomplete yet. We investigated short-term effects of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM 2.5 ) and ozone (O 3 ) on cardiac electrical impulse propagation and repolarization as recorded in surface electrocardiograms (ECG). Methods We analyzed repeated 12-lead ECG measurements performed on 5,332 patients between 2001 and 2012. The participants came from the Duke CATHGEN Study who underwent cardiac catheterization and resided in North Carolina, United States (NC, U.S.). Daily concentrations of PM 2.5 and O 3 at each participant’s home address were predicted with a hybrid air quality exposure model. We used generalized additive mixed models to investigate the associations of PM 2.5 and O 3 with the PR interval, QRS interval, heart rate-corrected QT interval (QTc), and heart rate (HR). The temporal lag structures of the associations were examined using distributed-lag models. Results Elevated PM 2.5 and O 3 were associated with four-day lagged lengthening of the PR and QRS intervals, and with one-day lagged increases in HR. We observed immediate effects on the lengthening of the QTc interval for both PM 2.5 and O 3 , as well as delayed effects for PM 2.5 (lagged by 3 – 4 days). The associations of PM 2.5 and O 3 with the PR interval and the association of O 3 with the QRS interval persisted until up to seven days after exposure. Conclusions In patients undergoing cardiac catheterization, short-term exposure to air pollution was associated with increased HR and delays in atrioventricular conduction, ventricular depolarization and repolarization.

ObjectivesChanges in air temperature are associated with an increase in cardiovascular events, but the role of procoagulant and proinflammatory blood markers is still poorly understood. The authors investigated the association between air temperature and fibrinogen, plasminogen activator inhibitor type 1, interleukin-6 and high-sensitivity C reactive protein in two potentially susceptible groups.MethodsThis prospective panel study was conducted between March 2007 and December 2008 in Augsburg, Germany. The study population comprised 187 participants with type 2 diabetes mellitus or impaired glucose tolerance and 87 participants with genetic polymorphisms on the detoxification and inflammation pathways. Overall, 1766 repeated blood measurements were collected. Hourly meteorology data were available from a central measurement site. The association between temperature and blood markers was analysed with additive mixed models.ResultsFor type 2 diabetes mellitus and impaired glucose tolerance participants, the authors observed immediate, lagged and cumulative increases in fibrinogen (range of percentage changes in geometric mean: 0.6%–0.8%) and plasminogen activator inhibitor type 1 (6.0%–10.1%) in association with a 5°C temperature decrement. Participants with a body mass index above 30 kg/m2 as well as females showed particularly strong fibrinogen effects. In participants with the special genetic background, 5°C decreases in the 5-day average of temperature led to a change of 8.0% (95% CI 0.5% to 16.2%) in interleukin-6 and of −8.4% (95% CI −15.8% to −0.3%) in high-sensitivity C reactive protein, the latter driven by physically active individuals.ConclusionsThe authors observed different temperature effects on blood markers in two potentially susceptible groups probably indicating varying underlying biological mechanisms. This study results might provide a link between temperature and cardiovascular events.