Unique Site Research Articles

Fire as an aesthetic resource in climate change communication: exploring the visual discourse of the California wildfires on Twitter/X

This article uses the case study of the California wildfires of 2020/2021 to examine the visual discourse on fires on social media and investigate how it was harnessed by environmental activists to shape narratives and meanings regarding climate change. The article draws on two datasets scraped from Twitter/X (350 images), i.e. the visual discourse of the California wildfires (250 images) and the visual data of environmental NGOs (100 images). Our findings show that the general visual discourse evokes the impact, risk, and devastation of wildfires. In contrast, in the second visual discourse, civil society deploys fire as an aesthetic resource to communicate danger but also makes an explicit connection between wildfires, climate change and fossil fuel reliance. Hence, our article highlights an urgent challenge in climate crisis communication: how to make an explicit causal link between wildfires and climate change through the use of visual images of fire. This challenge is exacerbated by dramatic and powerful images of fire which dominate social media, yet simultaneously undermine fire’s capacity to communicate blame and links to climate change. This tension is explored throughout the article with fire analysed as a unique site of contestation in the visual communication of climate change.

Creation and validation of the first infinium DNA methylation array for the human imprintome

BackgroundDifferentially methylated imprint control regions (ICRs) regulate the monoallelic expression of imprinted genes. Their epigenetic dysregulation by environmental exposures throughout life results in the formation of common chronic diseases. Unfortunately, existing Infinium methylation arrays lack the ability to profile these regions adequately. Whole genome bisulfite sequencing (WGBS) is the unique method able to profile the ICRs. However, it is very expensive and it requires not only a high coverage, but it is also computationally intensive to assess these regions.FindingsTo address this deficiency, we developed a custom methylation array containing 22,819 probes. Among them, 10,438 are CG probes targeting unique CpG sites, with 9,757 probes successfully mapping to 1,088 out of the 1,488 candidate ICRs recently described. To assess the performance of the array, we created matched samples processed with the Human Imprintome array and WGBS, which is the current standard method for assessing the methylation of the Human Imprintome. We compared the methylation levels from the shared CpG sites, and obtained a mean R2 = 0.569. We also created matched samples processed with the Human Imprintome array and the Infinium Methylation EPIC v2 array, and obtained a mean R2 = 0.796. Furthermore, replication experiments demonstrated high reliability (ICC: 0.799–0.945).ConclusionsOur custom array will be useful for replicable and accurate assessment, mechanistic insight, and targeted investigation of ICRs. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course.

Spatial patterns of coastal dune plant diversity reveal conservation priority hotspots in and out a network of protected areas

Effective conservation planning requires identifying priority hotspots to allocate resources. To preserve biodiversity, it is crucial to consider α, β and γ-diversity and protect the irreplaceable sites with high ecological uniqueness, which can host uncommon species assemblages that would be lost if only species-rich sites were protected. Coastal dunes, hosting highly specialized plant communities, are among the most threatened ecosystems worldwide. In this study, we identified conservation priority hotspots to assess the effectiveness of the network of protected areas in coastal dunes of Tuscany (central Italy), using data on plant communities collected in 506 plots. We additively partitioned γ-diversity in its α and β components, observing a significant variation at all spatial levels only for dune species. In terms of α-diversity, we found that Northern protected sites were richer in dune species, while synanthropic and alien species were equally present inside and outside protected areas of the region. By partitioning the total β-diversity into its components (replacement and richness difference), we found a prevalence of replacement for dune species, indicating the most unique sites as the ones to favor for conservation. Unique sites were identified through Local Contributions to Beta Diversity and their conservation value was determined by their species composition and the relationship with landscape variables. Unique sites with high conservation value were only partly protected, while some protected sites were altered and required restoration. Our approach proved effective for identifying the most unique sites, indicating some issues in the existing protected network, while providing valuable information on sites to prioritize for future conservation actions.

Reviews and syntheses: A scoping review evaluating the potential application of ecohydrological models for northern peatland restoration

Abstract. Peatland restoration and rehabilitation action has become more widely acknowledged as a necessary response to mitigating climate change risks and improving global carbon storage. Peatland ecosystems require restoration time spans of the order of decades and, thus, cannot be dependent upon the shorter-term monitoring often carried out in research projects. Hydrological assessments using geospatial tools provide the basis for planning restoration works as well as analysing associated environmental influences. “Restoration” encompasses applications to pre-restoration and post-restoration scenarios for both bogs and fens, across a range of environmental impact fields. The aim of this scoping review is to identify, describe, and categorize current process-based modelling uses in peatlands in order to investigate the applicability and appropriateness of ecohydrological and/or hydrological models for northern peatland restoration. Two literature searches were conducted using the entire Web of Science database in September 2022 and August 2023. Of the final 211 papers included in the review, models and their applications were categorized according to this review's research interests in seven distinct categories aggregating the papers' research themes and model outputs. Restoration site context was added by identifying 229 unique study site locations from the full database, which were catalogued and analysed against raster data for the Köppen–Geiger climate classification scheme. A majority of northern peatland sites were in temperate oceanic zones or humid continental zones that experienced snow. Over one in five models from the full database of papers were unnamed and likely intended for single use. Key themes emerging from topics covered by papers in the database included the following: modelling restoration development from a bog growth perspective, the prioritization of modelling greenhouse gas (GHG) emissions dynamics as a part of policymaking, the importance of spatial connectivity within or alongside process-based models to represent heterogeneous systems, and the increased prevalence of remote sensing and machine learning techniques to predict restoration progress with little physical site intervention. Models are presented according to their application to peatlands or broader ecosystem and organized from most to least complex. This review provides valuable context for the application of ecohydrological models in determining strategies for peatland restoration and evaluating post-intervention development over time.

Compositional-Dependent Structural Parameters and Energetics of Hibonite: Quantum-Chemical Investigation.

One of the first minerals to condense from the early solar nebula was hibonite (CaAl12O19), demonstrating a hexagonal crystal structure. There are five unique aluminum cation sites (M1-M5) in hibonite. Although hibonite contains aluminum, it can also have 3d transitional metals that substitute at aluminum cation sites, such as titanium, and other metals such as magnesium. Titanium can occur in multiple oxidation states, linking to redox conditions. A single substitution occurs when a single aluminum atom is replaced by a single titanium atom, causing the Ti to take on a 3+ oxidation state. On the other hand, Ti achieves an oxidation state of 4+ during a double substitution when a pair of aluminum atoms is replaced by a titanium and a magnesium atom. A density functional theory-based calculation is used to explore the relationship between the number of substitutions and the lattice parameters of the hibonite crystal. The calculated results reveal that the lengths of both unit cells (a and c) increase with an increasing number of single or double substitutions. The rate of increment per substitution depends on the cation sites, M1-M5, and substitution types. Along with the expansion of the unit cell of the hibonite due to the substitution, the substituted unit cell gains energy (and in turn stability) compared to the substituted unit cell without expansion, dependent on the lattice site and substitutions.

A Fundamental Perspective on the Selective Zn Substitution in Ternary Ordered Intermetallic Compound Cu6Zn2Sb2

AbstractThe unique site substitution of Zn in the structure of tetragonal and atomically ordered Cu6Zn2Sb2, followed by the formation of Cu5Zn3Sb2, has been addressed from fundamental perspectives. First principles energy calculations, and semi‐empirical electronic structure calculations using the density of states, crystal orbital Hamilton population, crystal orbital bond index and Mulliken population analysis were performed to understand the observed substitution pattern and the narrow homogeneity range of the titled compound. Mulliken and Löwdin's approach of charge analysis explain the experimentally proved ‘coloring’, based on the ‘site energy’ argument. The concept of ‘topological charge stabilization’ has been introduced in this context. Valence electron concentration and the optimization of the partially covalent Cu−Sb interactions also play pivotal role in the electronic stability of the titled phase.

Building Translator Repertoire Across a Humanitarian Translation App: Translingual Practice and Tarjimly

ABSTRACT This article creates a crowdsourced database for Tarjimly, a humanitarian translation app, based on recent technical communication and translingual research. The humanitarian translation app is a unique technological site that recruits volunteer translators to interpret for migrants and refugees. Tarjimly’s privacy policy prevents translators from building their translingual repertoire across the platform. This database allows translators to crowdsource their colloquial interpretations so that others may learn about regional, cultural, and dialectal translations from Tarjimly’s humanitarian audiences.

Unravelling nicotinic receptor and ligand features underlying neonicotinoid knockdown actions on the malaria vectormosquito Anopheles gambiae.

With the spread of resistance to long-established insecticides targeting Anopheles malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 Anopheles gambiae nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Agα1, Agα2, Agα3, Agα8 and Agβ1 subunits in Xenopus laevis oocytes, the Drosophila melanogaster orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Agα2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Agα3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Agα1/Agα2/Agα8/Agβ1 nAChR, their hydrophobicity and their rate of knockdown of adult female An. gambiae, providing new insights into neonicotinoid features important for malaria vector control.

ADP-ribosylome analysis reveals homogeneous DNA-damage-induced serine ADP-ribosylation across wild-type and BRCA-mutant breast cancer cell lines

ADP-ribosylation (ADPr) signaling plays a crucial role in DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage, poly(ADP-ribose) polymerase 1 (PARP1), are used to treat patients with breast cancer harboring BRCA1/2 mutations. However, resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To understand the role of ADPr in PARPi sensitivity, we use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze ADPr in six breast cancer cell lines exhibiting different PARPi sensitivities. We identify 1,632 sites on 777 proteins across all cell lines, primarily on serine residues, with site-specific overlap of targeted residues across DNA-damage-related proteins across all cell lines, demonstrating high conservation of serine ADPr-signaling networks upon DNA damage. Furthermore, we observe site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants and unique ADPr sites in PARPi-resistant BRCA-mutant HCC1937 cells, which have low poly(ADP-ribose) glycohydrolase (PARG) levels and longer ADPr chains on PARP1.

Revealing the ongoing speleogenetic processes in an underwater cave through the application of natural radionuclides and stable isotopes: case study from the hypogene Buda Thermal Karst

The underwater Molnár János Cave in the hypogene Buda Thermal Karst system (Budapest, Hungary) provides a unique site to study the effects of flowing groundwater and the interplay of fluids of different origin. The aim of the present study is to characterize the groundwater in different parts of the cave with temporal resolution, hence describe the recent speleogenetic processes within the cave. This study uses natural radioisotopes (uranium, radium, and radon) besides stable isotope ratios of oxygen and hydrogen to identify the different fluid components. The results show that the majority of the cave is situated in the flow path of the intermediate flow system, discharging in the Boltív Spring. Thus, the dominant recent speleogenetic processes are connected to this lukewarm groundwater. In contrast to previous views, typical hypogene processes, such as mixing corrosion involving thermal waters, are restricted to a narrower area in the cave, to the contact zone of lukewarm waters and the warmer upper water layer around the largest partially air-filled chamber (Kessler Hall). The warmer water layer is the result of free convection. In the air-filled chambers condensation-corrosion might be active. However, its effect is limited to the largest room (Kessler Hall), as it is open to surface conditions. More active mixing corrosion probably occurs deeper, in the area of the Northeastern Margin Fault, which is indicated by the radon content in the Boltív Spring. Regarding the temporal processes, the main driving force can be linked to the water level fluctuations of the Danube, which regulates the discharge of the regional flow-related thermal water upwelling, thus affecting the mixing ratio of the lukewarm waters transported by the intermediate flow systems and the thermal waters, representing the regional flow path, including basinal components.

Comprehensive Proteome and Acetylome Analysis of Needle Senescence in Larix gmelinii.

Leaf senescence is essential for the growth and development of deciduous trees in the next season. Larix gmelinii, a deciduous coniferous tree, exhibits its most distinctive feature by turning yellow in the autumn and eventually shedding its leaves, resulting in significant changes in its appearance during the fall. Lysine acetylation plays an important role in diverse cellular processes; however, limited knowledge is available regarding acetylations in the needle senescence of L. gmelinii. In this study, the proteomics and acetylated modification omics of two phenotypic leaves, yellow and green (senescent and non-senescent) needles, were analyzed before autumn defoliation. In total, 5022 proteins and 4469 unique acetylation sites in 2414 lysine acylated proteins were identified, and this resulted in the discovery of 1335 differentially expressed proteins (DEPs) and 605 differentially expressed acetylated proteins (DAPs) in yellow versus green needles. There are significant differences between the proteome and acetylome; only 269 proteins were found to be DEP and DAP, of which 136 proteins were consistently expressed in both the DEP and DAP, 91 proteins were upregulated, and 45 proteins were down-regulated. The DEPs participate in the metabolism of starch and sucrose, while the DAPs are involved in glycolysis and the tricarboxylic acid cycle. Among them, DEPs underwent significant changes in glycolysis and citric acid cycling. Most of the enzymes involved in glycolysis and the citrate cycle were acetylated. DAPs were down-regulated in glycolysis and up-regulated in the citrate cycle. In all, the results of this study reveal the important role of lysine acetylation in the senescence of L. gmelinii needles and provide a new perspective for understanding the molecular mechanism of leaf senescence and tree seasonal growth.

Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor.

Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

Synthesis and antibacterial action of 3’,6’-disubstituted spectinomycins

Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6’-position to produce trospectomycin and to the 3’-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3’,6’-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3’-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

Individual from the kurgan burial of the XII century in the Middle Oka — experience of complex archaeological and genetic research

For the first time, this paper presents a complex study of the burial of the ancient Russian woman from the classic “Vyatich” mound from the Kremenyie burial site (Moscow region). The mounds and synchronized ground cremation burials are combined at this unique 12th-century burial site. The aim of this research is to examine the historical details of the person from the mound using conventional archaeological, anthropological, and archae-oparasitology methodologies along with modern paleogenetics methods. The burial site is characterized by a general “archaic” rite, manifested in the late preservation of the cremation rite along with the burial. According to anthropological data, an elderly woman, over forty, was buried there. She was identified as a member of the local population by radiogenic strontium isotope (87Sr/86Sr) study. Rich grave content and the fact that the body was buried in the middle of the mound indicate the woman's high social standing in the community. According to ar-chaeoparasitological data, the eating habits of the woman appear to be characterized by the consumption of un-cooked or insufficiently thermally prepared freshwater fish. The complete mtDNA sequence reconstruction indi-cates that it belongs to haplogroup V1a1, one of the Western Eurasian haplogroup V branches. To date, this represents the first case of the V1a1 mitogroup being found in the Russian Plain during ancient times. A repre-sentative of the Danish Viking clan from the Oxford burial site of the XI century was the closest of the ancient samples to the mtDNA of the studied woman, which indicates a genetic relationship on the maternal lineage with the medieval Northwestern European population. Single nucleotide substitution A7299G in the mitogenome of the woman clusters her with present-day Russians from the Belgorod and Pskov regions and shows the continuity of the modern Russian population with the Ancient Russians. Thus, the results of our study demonstrate the private details of the individual as common historical features, which include the ceremonial side of burial and belonging to the maternal genetic lineage preserved in the modern gene pool of the Russian population.

Phytosociological Analysis of Bumdeling Ramsar site, Riverine Wetland of International Importance, Eastern Bhutan

The Kholongchu riverine wetlands in Bumdeling, Bhutan, are a unique ramsar site and crucial winter roosting grounds for the Black Necked Crane. Despite the area's notable ecological successions, recent information on plant diversity is less known from the wetland. In 2023, study was conducted to evaluate the phytodiversity and phytosociology of the Bumdeling Ramsar site (BRS) using quantitative quadrat analysis method. The study identified 165 plant species in a wetland, with Asteraceae being the most dominant family. Herbaceous plants dominate the wetland, followed by shrubs and grasses. The area has moderate floral species diversity with Simpson (0.87) and Shannon (2.59) diversity value. Floral species are evenly distributed, with no single species dominating vegetation with Simpson dominance (0.13). Menhinicks index (2.19) and Margalef (4.60) index indicate high species richness. Furthermore, Important Value Index indicated Persicaria hydropiper, Anaphalis margaritaceae, and Alnus nepalensis as the dominating and important plant species in the wetland. This study provides valuable floristic information for further scientific studies and management activities in BRS.

Occurrence of a “forever chemical” in the atmosphere above pristine Amazon Forest

Per- and polyfluoroalkyl substances (PFAS), often referred to as “forever chemicals”, are a class of man-made, extremely stable chemicals, which are widely used in industrial and commercial applications. Exposure to some PFAS is now known to be detrimental to human health. By virtue of PFAS long residence times, they are widely detected in the environment, including remote locations such as the Arctics, where the origin of the PFAS is poorly understood. It has been suggested that PFAS may be transported through contaminated waters, leading to accumulation in coastal areas, where they can be aerosolised via sea spray, thereby extending their geographical distribution far beyond their original source regions.The aim of this work is to investigate, for the first time, whether “forever chemicals” could be transported to areas considered to be pristine, far from coastal sites. This study was performed at the Amazonian Tall Tower Observatory (ATTO), a unique remote site situated in the middle of the Amazon rainforest, where a restricted PFAS, perfluorooctanoic acid (PFOA), was observed with concentrations reaching up to 2 pg/m3. A clear trend of increasing concentration with sampling height was observed and air masses from the south over Manaus had the highest concentrations. Atmospheric lifetime estimations, removal mechanisms supported by measurements at two heights (320 and 42 m above the rainforest), and concentration spikes indicated a long-range transport of PFOA to pristine Amazon rainforest. Potential sources, including industrial activities in urban areas, were explored, and historical fire management practices considered.This research presents the first measurements of PFAS in the atmosphere of Amazon rainforest. Remarkably, even in this remote natural environment, appreciable levels of PFAS can be detected. This study provides valuable insights into the long-range transport of the anthropogenic “forever chemical” into a remote natural ecosystem and should raise awareness of potential environmental implications.

Global profiling of functional histidines in live cells using small-molecule photosensitizer and chemical probe relay labelling.

Recent advances in chemical proteomics have focused on developing chemical probes that react with nucleophilic amino acid residues. Although histidine is an attractive candidate due to its importance in enzymatic catalysis, metal binding and protein-protein interaction, its moderate nucleophilicity poses challenges. Its modification is frequently influenced by cysteine and lysine, which results in poor selectivity and narrow proteome coverage. Here we report a singlet oxygen and chemical probe relay labelling method that achieves high selectivity towards histidine. Libraries of small-molecule photosensitizers and chemical probes were screened to optimize histidine labelling, enabling histidine profiling in live cells with around 7,200 unique sites. Using NMR spectroscopy and X-ray crystallography, we characterized the reaction mechanism and the structures of the resulting products. We then applied this method to discover unannotated histidine sites key to enzymatic activity and metal binding in select metalloproteins. This method also revealed the accessibility change of histidine mediated by protein-protein interaction that influences select protein subcellular localization, underscoring its capability in discovering functional histidines.

An Unbiased Proteomic Platform for Activity-based Arginylation Profiling.

Protein arginylation is an essential posttranslational modification (PTM) catalyzed by arginyl-tRNA-protein transferase 1 (ATE1) in mammalian systems. Arginylation features a post-translational conjugation of an arginyl to a protein, making it extremely challenging to differentiate from translational arginine residues with the same mass in a protein sequence. Here we present a general activity-based arginylation profiling (ABAP) platform for the unbiased discovery of arginylation substrates and their precise modification sites. This method integrates isotopic arginine labeling into an ATE1 assay utilizing biological lysates (ex vivo) rather than live cells, thus eliminating translational bias derived from the ribosomal activity and enabling bona fide arginylation identification using isotopic features. ABAP has been successfully applied to an array of peptide, protein, cell, patient, and animal tissue samples using 20 μg sample input, with 229 unique arginylation sites revealed from human proteomes. Representative sites were validated and followed up for their biological functions. The developed platform is globally applicable to the aforementioned sample types and therefore paves the way for functional studies of this difficult-to-characterize protein modification.

Randomized controlled, open-label, phase IIb/III study of lurbinectedin in combination with doxorubicin versus doxorubicin alone as first-line treatment in patients with metastatic leiomyosarcoma.

TPS11590 Background: Lurbinectedin (LUR) is a synthetic chemical entity structurally related to trabectedin that inhibits oncogenic transcription and is active in tumors addicted to transcription. Synergistic activity of the combination of LUR with Doxorubicin (DOX) was found in solid tumors. Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at different doses. In a phase 2 trial in soft tissue sarcoma (STS) patients (pts) (mostly with LMS: 12/20 pts), a combination of DOX 50 mg/m2 + LUR 2 mg/m2 Day (D)1 q3wk resulted in a response rate (RR) of 35% (4/7 LMS pts responding) and a disease control rate (DCR) at 24 wks of 40% (1). A phase 1b/2 trial in 10 advanced STS pts found a RR of 60% (5 were LMS, with 3 partial responses) treated at DOX 25 mg/m2 D1 or D1,D8 + LUR 3.2 mg/m2 D1 q3wk, (2). The promising results of these trials provide a rationale for further exploring this combination in a phase 2b/3 trial as first-line therapy for metastatic LMS (SaLuDo - NCT06088290). Methods: SaLuDo is a randomized, open-label study evaluating LUR in combination with DOX compared to DOX alone as first-line treatment of pts with metastatic LMS. The primary endpoint is progression-free survival (PFS) according to Independent Radiological committee (IRC). Secondary endpoints include overall survival, PFS according to Investigator assessment (IA), overall response rate, duration of response, and clinical benefit rate (according to IRC and IA), safety profile, patient-reported outcomes, pharmacokinetics, and exploratory pharmacogenomic analysis. Main inclusion criteria include age ≥ 18 years, confirmed diagnosis of metastatic LMS, and no prior systemic treatment for metastatic disease. Exclusion criteria include prior treatment with anthracyclines, lurbinectedin or trabectedin. The phase 2b part of the study will randomize approximately 120 pts into 3 arms (1:1:1): Control arm (DOX 75 mg/m2 D1 q3wk; experimental ARM A (DOX 50 mg/m2 D1 + LUR 2.2 mg/m2 D1 + 1ry GCSF prophylaxis q3wk), and experimental ARM B (DOX 25 mg/m2 D1 + LUR 3.2mg/m2 D1 + 1ry GCSF prophylaxis q3wk). Stratification will be done according to site of primary tumor (uterine vs. soft tissue), sites of metastatic disease (lung as unique site vs. other) and time from diagnosis to study entry (≤ 12 months vs. >12 months). One of the two experimental arms will be dropped out at the end of phase 2b. The study will then enter the phase 3 part and approximately 120 pts will be randomized 1:1 between the control arm and the selected experimental arm. An Independent Data Monitoring Committee will oversee the conduct of the study. The first patient was randomized in 09/2023. The phase 2b part of the study is ongoing and recruiting patients in Europe and the USA. 1. Cote EJC 2020; 126:21-32. 2. Cote. JCO 2023; 41: Abst 11507. Clinical trial information: NCT06088290 .

Generalized functionals for qualification of geological carbon storage injection sites

Many nations have pledged to reach carbon neutrality by 2050. Embarking on the decarbonization journey, they posited geological carbon storage (GCS) as a pivotal technology within the carbon capture, utilization, and storage (CCUS) framework. The CCUS chain operates to reduce “hard-to-abate” emissions at key sectors by capturing carbon dioxide (CO2), reusing it, transporting it, or disposing of it via injection into underground geological formations for permanent storage. Despite the global success of GCS ventures, mainly driven by the oil and gas industry, GCS initiatives are still in their early stages in several developing countries. In Brazil, for instance, a full setup covering precise storage capacity databases, potential CCUS clusters, national regulatory structure, and auxiliary computer-aided engineering is underway. Intended to push the frontier in the latter subject, this paper introduces mathematical models for qualifying underground CO2 storage sites. Our research explores a family of multivariate functionals endowed with underlying reservoir features and distinct weighting functions, thus envisioning two primary objectives. Firstly, it clarifies non-linear interactions between rock and fluid properties using quality indicators. Secondly, it evaluates geographical regions considering structural traps/caprocks settings. Backed by the Matlab Reservoir Simulation Toolbox (MRST) capabilities, the methodology is a subsidiary resource for identifying suitable injection and storage sites. A case study using the UNISIM-I-D model generated dozens of volumetric quality maps that point to unique potential storage sites. Numerical simulation experiments of injection comparing legacy and novel wells reveal storage surpluses improved by up to 50%. The paper seeks to establish foundational knowledge in GCS efficiency for general underground settings. One expects that these outcomes leverage well-repurposing perspectives and stimulate field appraisal actions to scale up GCS projects both in Brazil and worldwide.