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As a key material for manufacturing clean energy technologies, steel is crucial for energy transition, but its production causes 2.6 Gton of CO 2 emissions at global level each year. In 2020 the European Union (EU) set a net-zero emissions target by 2050, fostering innovation in the steel industry to reduce its environmental impact. However, a scenario-oriented and technologically comprehensive analysis assessing prospected environmental and market implications of steel decarbonisation strategies remains a gap, which is addressed in this paper. The analysis adopts a hybrid input-output-based life-cycle assessment model built in the MARIO framework, extending the Exiobase database to represent the supply chains of the most promising low-carbon steelmaking technologies in the EU, such as hydrogen- or charcoal-injected blast furnaces and natural gas- and hydrogen-based direct reduction routes. The penetration of these technologies is explored by formulating scenarios resembling European climate targets. The results show a reduction in the carbon footprint of steel across all scenarios, ranging up to −26% in 2030 and to −60% in 2050. However, the extent of footprint reduction is highly dependent on the share of clean electricity in the European supply mix, highlighting the relevance of holistic decarbonisation strategies. Economic implications affect steel prices, which rise up to 25% in 2030 and 56% in 2050, opening discussions on the need for suitable policies such as CBAM to avoid protectionism and encourage international technological progress.

Access to affordable, reliable, and modern energy remains a critical goal under the Agenda 2030 for Sustainable Development, especially in remote areas of developing countries. Based on traditional engineering approaches, many energy solution planning tools have been developed to identify the optimal solution in these areas to assess the competition across different technological options. Nevertheless, these approaches, based on an economic optimum, do not necessarily grant long-term sustainability of the solution in specific local contexts, since they are not able to capture the social implications within the Energy-Development nexus. Moreover, also in light of the 2030 Agenda, scientific and grey literature on energy access highlights how energy solutions planning methodologies developed in the last decades need to be complemented by a more comprehensive view, able to integrate evidence from various disciplines, especially engineering and social sciences. Based on the above considerations, this paper introduces a novel framework under the name of CESP, where three social sciences-based phases complement three engineering phases, each one characterized by specific tools, to offer an informed decision framework for the local planner. CESP encompasses a set of techno-economic and socio-technical actions to prevent potential failure as evidenced by a counterfactual analysis used to identify the reasons behind past project failures. The CESP framework presents a sequential and iterative structure that underlines the cyclic perspective of a holistic decision process where social sciences feed the engineering analysis and vice versa. Finally, CESP emerges as a practical and applicable framework for supporting energy access planning in critical areas.

Globally about 800 million people live without electricity at home, over two thirds of which are in sub-Saharan Africa. Planning electricity access infrastructure and allocating resources efficiently requires a careful assessment of the diverse energy needs across space, time, and sectors. Because of data scarcity, most country or regional-scale electrification planning studies have however assumed a spatio-temporally homogeneous (top-down) potential electricity demand. Poorly representing the heterogeneity in the potential electricity demand across space, time, and energy sectors can lead to inappropriate energy planning, inaccurate energy system sizing, and misleading cost assessments. Here we introduce M-LED, a Multi-sectoral Latent Electricity Demand geospatial data processing platform to estimate electricity demand in communities that live in energy poverty. The platform shows how big data and bottom-up energy modelling can be leveraged together to represent the potential electricity demand with high spatio-temporal and sectoral granularity. We apply the methodology to Kenya as a country-study and devote specific attention to the implications for water-energy-agriculture-development interlinkages. A more detailed representation of the demand-side in large-scale electrification planning tools bears a potential for improving energy planning and policy.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17, and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of S1P or cytokine signaling in astrocytes via BAF312 prevented neurons from astrocyte-induced degeneration. Overall, these experiments on human astrocytes suggest that during neuroinflammation targeting of S1P1 via BAF312 may modulate key astrocyte functions and thereby attain neuroprotection indirectly.

Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.

In state-of-the-art energy systems modelling, reservoir hydropower is represented as any other thermal power plant: energy production is constrained by the plant’s installed capacity and a capacity factor calibrated on the energy produced in previous years. Natural water resource variability across different temporal scales and the subsequent filtering effect of water storage mass balances are not accounted for, leading to biased optimal power dispatch strategies. In this work, we aim at introducing a novelty in the field by advancing the representation of reservoir hydropower generation in energy systems modelling by explicitly including the most relevant hydrological constraints, such as time-dependent water availability, hydraulic head, evaporation losses, and cascade releases. This advanced characterization is implemented in an open-source energy modelling framework. The improved model is then demonstrated on the Zambezi River Basin in the South Africa Power Pool. The basin has an estimated hydropower potential of 20,000 megawatts (MW) of which about 5,000 MW has been already developed. Results show a better alignment of electricity production with observed data, with a reduction of estimated hydropower production up to 35% with respect to the baseline Calliope implementation. These improvements are useful to support hydropower management and planning capacity expansion in countries richly endowed with water resource or that are already strongly relying on hydropower for electricity production.

As it emerges from the literature, electricity access in rural contexts is deeply intertwined with socioeconomic dynamics. However, the advent of a reliable and sufficient source of electricity is not the sole driver that might contribute to local development. Indeed, complementary activities might have a crucial role in sustaining the development of rural communities as well as the electricity access. The current research addresses the lack of counterfactual scenarios in which the impact of complementary activities on electrification projects can be investigated. The authors introduce the case study of Matembwe village, a rural community in the Njombe region of Tanzania. The data collection includes the electricity consumption, number of electricity connections, and number of income-generating activities in a timespan ranging from 1989 to 2015. The analysis is based on system dynamics. The study considers different scenarios representing the dynamics related to the following complementary actions: access to market measures, access to credit measures, and access to usable skills. On the one hand, the study reveals that the effectiveness of the considered complementary actions is limited except from the access to microcredit which fosters an increase in electricity connections by 17%. On the other hand, both access to microcredit and the starting up of a local cooperative by CEFA Onlus that reinvests its profits in the local market impact the socio-economic dimension by 69% and 22%, respectively.

Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR’s impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors. Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.

Long-read sequencing allows analyses of single nucleic-acid molecules and produces sequences in the order of tens to hundreds kilobases. Its application to whole-genome analyses allows identification of complex genomic structural-variants (SVs) with unprecedented resolution. SV identification, however, requires complex computational methods, based on either read-depth or intra- and inter-alignment signatures approaches, which are limited by size or type of SVs. Moreover, most currently available tools only detect germline variants, thus requiring separate computation of sample pairs for comparative analyses. To overcome these limits, we developed a novel tool (Germline And SOmatic structuraL varIants detectioN and gEnotyping; GASOLINE) that groups SV signatures using a sophisticated clustering procedure based on a modified reciprocal overlap criterion, and is designed to identify germline SVs, from single samples, and somatic SVs from paired test and control samples. GASOLINE is a collection of Perl, R and Fortran codes, it analyzes aligned data in BAM format and produces VCF files with statistically significant somatic SVs. Germline or somatic analysis of 30 × sequencing coverage experiments requires 4–5 h with 20 threads. GASOLINE outperformed currently available methods in the detection of both germline and somatic SVs in synthetic and real long-reads datasets. Notably, when applied on a pair of metastatic melanoma and matched-normal sample, GASOLINE identified five genuine somatic SVs that were missed using five different sequencing technologies and state-of-the art SV calling approaches. Thus, GASOLINE identifies germline and somatic SVs with unprecedented accuracy and resolution, outperforming currently available state-of-the-art WGS long-reads computational methods.

Whether Clonal Hematopoiesis (CH) represents a risk factor for severity of the COVID-19 disease remains a controversial issue. We report the first high- sensitivity analysis of CH in COVID-19 patients (threshold of detection at 0.5% vs 1 or 2% in previous studies). We analyzed 24 patients admitted to ICU for COVID-19 (COV-ICU) and 19 controls, including healthy subjects and asymptomatic SARS-CoV2-positive individuals. Despite the significantly higher numbers of CH mutations identified (80% mutations with <2% variant allele frequency, VAF), we did not find significant differences between COV-ICU patients and controls in the prevalence of CH or in the numbers, VAF or functional categories of the mutated genes, suggesting that CH is not overrepresented in patients with COVID-19. However, when considering potential drivers CH mutations (CH-PD), COV-ICU patients showed higher clonal complexity, in terms of both mutation numbers and VAF, and enrichment of variants reported in myeloid neoplasms. However, we did not score an impact of increased CH-PD on patient survival or clinical parameters associated with inflammation. These data suggest that COVID-19 influence the clonal composition of the peripheral blood and call for further investigations addressing the potential long-term clinical impact of CH on people experiencing severe COVID-19. We acknowledge that it will indispensable to perform further studies on larger patient cohorts in order to validate and generalize our conclusions. Moreover, we performed CH analysis at a single time point. It will be necessary to consider longitudinal approaches with long periods of follow-up in order to assess if the COVID-19 disease could have an impact on the evolution of CH and long-term consequences in patients that experienced severe COVID-19.