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Abstract Patients who develop chimeric antigen receptor (CAR) T-cell-related immune effector cell-associated neurotoxicity syndrome (ICANS) frequently undergo evaluation with electroencephalography (EEG). We hypothesize that EEG features and Synek scale score, a measure of degree of EEG abnormality, are associated with ICANS severity. Here, we performed a retrospective review of 125 adult patients at Memorial Sloan Kettering Cancer Center (MSKCC) who received CAR-T cell therapy from 2010 to 2019, including 53 patients with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 72 patients with large B-cell lymphoma (LBCL) treated with the commercial CAR T products axicabtagene ciloleucel or tisagenlecleucel. We collected video EEG monitoring (27 with B-ALL and 20 with LBCL) and recorded daily EEG features, Synek scores, and ICANS grade for 47 eligible patients. Synek scale and ICANS grade were positively correlated (correlation coefficient 0.47, 95% CI: 0.31–0.60). This was further corroborated in the univariable model associating high Synek scale (3 or 4) with high ICANS grade (OR = 15.2; 95%CI:7.8–29.7, p

Abstract Coronary artery disease (CAD) is characterized by narrowing and subsequent blockade of coronary arteries, and imposes a significant health and economic burden. Stent and scaffold devices are introduced in advanced CAD to improve vascular stability and restore blood flow. Although in vitro flow systems like the Chandler loop have been developed to enhance the understanding of interactions between device materials, their coatings, and vascular cells, imaging-based in vitro analysis of device performance is limited. In this study, we established a novel stent flow chamber system designed to assess the thrombogenicity of bioresorbable magnesium scaffold (RMS) and stent materials in vitro. Additionally, we compared the thrombogenicity – an important clinical parameter in stent performance – of the Magmaris-316 L stainless steel stent with its predecessors, Magmaris RMS and a prototype of the third-generation RMS (DREAMS 3G). Analysis of platelet adhesion and coverage of the different devices under flow conditions demonstrated that the Magmaris RMS exhibits reduced thrombogenicity compared to the Magmaris-316 L stainless steel stent. Moreover, thrombogenicity of the DREAMS 3G prototype, composed of BIOmag material, is further decreased compared to its predecessors. The observed reduction in thrombogenicity of the DREAMS 3G prototype in vitro suggests additional improvements in clinical safety and efficacy, highlighting its promise for treating CAD. Future research on this prototype may thus open avenues for analyzing other blood components and patient-derived endothelial cells. In line with the 3R principles, this approach may also help reduce the need for animal testing.

Abstract BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Abstract Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS SMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS Smarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS SMARCB1- within the TME.

Abstract This study introduces a comprehensive approach for classifying individual malting barley kernels, involving dual-sided kernel imaging, a specifically designed image processing algorithm, an optimized deep neural network architecture, and a mechanical sorting system. The proposed method achieves precise classification into multiple classes, aligning with quality standards for malting material assessment. Throughout the study, various image analysis techniques were assessed, including traditional feature engineering, established transfer learning deep neural network architectures, and our custom-designed convolutional neural network tailored for barley kernel image analysis. Comparative analysis underscores the superior performance of our network model. The study reveals that our proposed deep learning network achieves a 94% accuracy in classifying barley kernel defects and varieties, outperforming well-established transfer learning models to complex architectures that attain 93% accuracy. Additionally, it surpasses the traditional machine learning approach involving feature extraction and support vector machine classifiers, which achieve accuracy below 90% in detecting defective kernels and below 70% in varietal classification. However, we also noted the traditional approach’s advantage in morphological feature recognition. This observation guides new research toward integrating morphological feature extraction techniques with modern convolutional networks. This paper presents a deep neural network designed specifically for the analysis of cereal kernel images in two applications: defect and variety classification. It emphasizes the importance of standardizing kernel orientation and merging images from both sides of the kernel, and introduces a device for image acquisition that fulfills this need.

Abstract Borna disease virus 1 (BoDV-1) is the causative agent of Borna disease, a fatal neurologic disorder of domestic mammals and humans, resulting from spill-over infection from its natural reservoir host, the bicolored white-toothed shrew (Crocidura leucodon). The known BoDV-1-endemic area is remarkably restricted to parts of Germany, Austria, Switzerland and Liechtenstein. To gain comprehensive data on its occurrence, we analysed diagnostic material from suspected BoDV-1-induced encephalitis cases based on clinical and/or histopathological diagnosis. BoDV-1 infection was confirmed by RT-qPCR in 207 domestic mammals, 28 humans and seven wild shrews. Thereby, this study markedly raises the number of published laboratory-confirmed human BoDV-1 infections and provides a first comprehensive summary. Generation of 136 new BoDV-1 genome sequences from animals and humans facilitated an in-depth phylogeographic analysis, allowing for the definition of risk areas for zoonotic BoDV-1 transmission and facilitating the assessment of geographical infection sources. Consistent with the low mobility of its reservoir host, BoDV-1 sequences showed a remarkable geographic association, with individual phylogenetic clades occupying distinct areas. The closest genetic relatives of most human-derived BoDV-1 sequences were located at distances of less than 40 km, indicating that spill-over transmission from the natural reservoir usually occurs in the patient´s home region.

Abstract This study aimed to evaluate the impact of contrast media application on CT attenuation of the bone using a novel calcium-only imaging technique (VCa) from dual-layer spectral detector CT (DLCT), which enables CT-based bone mineral density measurement unimpeded by soft tissue components. For this, true non-contrast (TNC) and venous phase images (VP) of n = 97 patients were acquired. CT attenuation of the first lumbar vertebra (L1) was measured in TNC-VCa, VP-VCa, and in virtual non-contrast images (VNC). CT attenuation was significantly higher in VP-VCa than in TNC-VCa (p

Abstract Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

Abstract Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Abstract Jamaican fruit bats (Artibeus jamaicensis) naturally harbor a wide range of viruses of human relevance. These infections are typically mild in bats, suggesting unique features of their immune system. To better understand the immune response to viral infections in bats, we infected male Jamaican fruit bats with the bat-derived influenza A virus (IAV) H18N11. Using comparative single-cell RNA sequencing, we generated single-cell atlases of the Jamaican fruit bat intestine and mesentery. Gene expression profiling showed that H18N11 infection resulted in a moderate induction of interferon-stimulated genes and transcriptional activation of immune cells. H18N11 infection was predominant in various leukocytes, including macrophages, B cells, and NK/T cells. Confirming these findings, human leukocytes, particularly macrophages, were also susceptible to H18N11, highlighting the zoonotic potential of this bat-derived IAV. Our study provides insight into a natural virus-host relationship and thus serves as a fundamental resource for future in-depth characterization of bat immunology.

Abstract Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Abstract As immunohistochemistry is valuable for determining tissue and cell tropism of avian influenza viruses (AIV), but time-consuming, an artificial intelligence-based workflow was developed to automate the AIV antigen quantification. Organ samples from experimental AIV infections including brain, heart, lung and spleen on one slide, and liver and kidney on another slide were stained for influenza A-matrixprotein and analyzed with QuPath: Random trees algorithms were trained to identify the organs on each slide, followed by threshold-based quantification of the immunoreactive area. The algorithms were trained and tested on two different slide sets, then retrained on both and validated on a third set. Except for the kidney, the best algorithms for organ selection correctly identified the largest proportion of the organ area. For most organs, the immunoreactive area assessed following organ selection was significantly and positively correlated to a manually assessed semiquantitative score. In the validation set, intravenously infected chickens showed a generally higher percentage of immunoreactive area than chickens infected oculonasally. Variability between the slide sets and a similar tissue texture of some organs limited the ability of the algorithms to select certain organs. Generally, suitable correlations of the immunoreactivity data results were achieved, facilitating high-throughput analysis of AIV tissue tropism.

Abstract A series of new pyrazolate and mixed pyrazolate/pyrazole magnesium complexes is described and their reactivity toward carbon dioxide is examined. The dimeric complex [Mg(pztBu,tBu)2]2 inserts CO2 instantly and quantitatively forming the tetrameric complex [Mg(CO2·pztBu,tBu)2]4 and monomeric donor‐stabilized [Mg(CO2·pztBu,tBu)2(thf)2]. Complexes of the type [Mgx(pzR,R)2x(HpzR,R)y]n (R = iPr, tBu) engage in similar insertion reactions involving dissociation of the carbamic acid HOOCpzR,R. Even solid polymeric derivatives [Mg(pzR,R)2]n (R = Me, H) react instantaneously and exhaustively with CO2, the resulting [Mg(CO2·pz)2]m featuring a CO2 capacity of 35.7 wt% (8.2 mmol g−1). All described magnesium pyrazolates display completely reversible CO2 uptake in solution and in the solid state, respectively, as monitored via VT 1H NMR and in situ FTIR spectroscopy as well as thermogravimetric analysis. Fluorinated [Mg2(pzCF3,CF3)4(thf)3] does not yield any isolable CO2 insertion product but exhibits the highest activity in the catalytic transformation of epoxides and CO2 to cyclic carbonates.

Abstract Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women’s Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African Americans by > 64% compared to alternative methods, and even outperforms PRS-CSx with large European GWAS for some scenarios. We believe GAUDI will be a valuable tool to mitigate disparities in PRS performance in admixed individuals.

Abstract Achieving low-carbon development of the cement industry in the developing countries is fundamental to global emissions abatement, considering the local construction industry’s rapid growth. However, there is currently a lack of systematic and accurate accounting and projection of cement emissions in developing countries, which are characterized with lower basic economic country condition. Here, we provide bottom-up quantifications of emissions from global cement production and reveal a regional shift in the main contributors to global cement CO2 emissions. The study further explores cement emissions over 2020-2050 that correspond to different housing and infrastructure conditions and emissions mitigation options for all developing countries except China. We find that cement emissions in developing countries except China will reach 1.4-3.8 Gt in 2050 (depending on different industrialization trajectories), compared to their annual emissions of 0.7 Gt in 2018. The optimal combination of low-carbon measures could contribute to reducing annual emissions by around 65% in 2050 and cumulative emissions by around 48% over 2020-2050. The efficient technological paths towards a low carbon future of cement industry vary among the countries and infrastructure scenarios. Our results are essential to understanding future emissions patterns of the cement industry in the developing countries and can inform policies in the cement sector that contribute to meeting the climate targets set out in the Paris Agreement.

Abstract In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10−11 and 3.74×10−2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.

Abstract Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.

Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.

Abstract Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p

Abstract Monitoring subnational healthcare quality is important for identifying and addressing geographic inequities. Yet, health facility surveys are rarely powered to support the generation of estimates at more local levels. With this study, we propose an analytical approach for estimating both temporal and subnational patterns of healthcare quality indicators from health facility survey data. This method uses random effects to account for differences between survey instruments; space-time processes to leverage correlations in space and time; and covariates to incorporate auxiliary information. We applied this method for three countries in which at least four health facility surveys had been conducted since 1999 – Kenya, Senegal, and Tanzania – and estimated measures of sick-child care quality per WHO Service Availability and Readiness Assessment (SARA) guidelines at programmatic subnational level, between 1999 and 2020. Model performance metrics indicated good out-of-sample predictive validity, illustrating the potential utility of geospatial statistical models for health facility data. This method offers a way to jointly estimate indicators of healthcare quality over space and time, which could then provide insights to decision-makers and health service program managers.

The intracellular protozoan parasite Leishmania causes leishmaniasis in humans, leading to serious illness and death in tropical and subtropical areas worldwide. Unfortunately, due to the unavailability of approved vaccines for humans and the limited efficacy of available drugs, leishmaniasis is on the rise. A comprehensive understanding of host-pathogen interactions at the molecular level could pave the way to counter leishmaniasis. There is growing evidence that several intracellular pathogens target RNA interference (RNAi) pathways in host cells to facilitate their persistence. The core elements of the RNAi system are complexes of Argonaute (Ago) proteins with small non-coding RNAs, also known as RNA-induced silencing complexes (RISCs). Recently, we have shown that Leishmania modulates Ago1 protein of host macrophages for its survival. In this study, we biochemically characterize the Ago proteins' interactome in Leishmania-infected macrophages compared to non-infected cells. For this, a quantitative proteomic approach using stable isotope labelling by amino acids in cell culture (SILAC) was employed, followed by purification of host Ago-complexes using a short TNRC6 protein-derived peptide fused to glutathione S-transferase beads as an affinity matrix. Proteomic-based detailed biochemical analysis revealed Leishmania modulated host macrophage RISC composition during infection. This analysis identified 51 Ago-interacting proteins with a broad range of biological activities. Strikingly, Leishmania proteins were detected as part of host Ago-containing complexes in infected cells. Our results present the first report of comprehensive quantitative proteomics of Ago-containing complexes isolated from Leishmania-infected macrophages and suggest targeting the effector complex of host RNAi machinery. Additionally, these results expand knowledge of RISC in the context of host-pathogen interactions in parasitology in general.

Abstract Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.

Abstract The consistent monitoring of trees both inside and outside of forests is key to sustainable land management. Current monitoring systems either ignore trees outside forests or are too expensive to be applied consistently across countries on a repeated basis. Here we use the PlanetScope nanosatellite constellation, which delivers global very high-resolution daily imagery, to map both forest and non-forest tree cover for continental Africa using images from a single year. Our prototype map of 2019 (RMSE = 9.57%, bias = −6.9%). demonstrates that a precise assessment of all tree-based ecosystems is possible at continental scale, and reveals that 29% of tree cover is found outside areas previously classified as tree cover in state-of-the-art maps, such as in croplands and grassland. Such accurate mapping of tree cover down to the level of individual trees and consistent among countries has the potential to redefine land use impacts in non-forest landscapes, move beyond the need for forest definitions, and build the basis for natural climate solutions and tree-related studies.

Abstract Cancer metastasis to the brain is a significant clinical problem. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. We further confirm that the IFN response in astrocytes facilitates brain metastasis. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) reduces brain metastases. Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.

Abstract The objective was to examine pandemic-related changes in depression and anxiety symptoms in adolescents and young adults in Germany considering pre-existing depression and anxiety problems. In this cross-sectional study, 11,523 adolescents and young adults aged 14–21 years who perceived an impact of the Coronavirus disease (COVID-19) pandemic on their mental health reported the frequencies of depression and anxiety symptoms retrospectively for different pre-pandemic and pandemic phases. Data were collected using web-based questionnaires between January 5th and February 20th, 2022. Depression and anxiety were assessed with a modified version of the Patient Health Questionnaire (PHQ-4). Scale-fit cut-offs were used to identify pre-existing elevated depression and anxiety scores. Multilevel mixed linear models were conducted to assess changes in depression and anxiety symptoms from 2019 to 2021 and compare for age, gender and pre-pandemic mental health problems. Among young people who were experiencing mental health changes as a result of the pandemic, the frequency of depression and anxiety symptoms increased during the COVID-19 pandemic. This association was moderated by age, gender, and pre-existing elevated depression/anxiety scores. For young people without elevated pre-pandemic depression/anxiety, the scores increased strongly over time, with 61% reporting elevated depression symptoms and 44% reporting elevated anxiety symptoms in 2021. In contrast, self-perceived change was minimal for adolescents and young adults with elevated pre-pandemic depression and anxiety. Among young people whose mental health has been affected by the COVID-19 pandemic, the group without pre-pandemic mental health conditions reported greater deterioration than those with elevated pre-pandemic depression and anxiety scores. Thus, adolescents and young adults without pre-existing depression and anxiety problems who perceived a change in general mental health due to the pandemic reported an alarming increase in symptoms of depression and anxiety during the COVID-19 pandemic period.

In its business-as-usual scenario, the 1972 Club-of-Rome report—The Limits to Growth—describes the collapse of the world economy around the year 2030, either because of the scarcity of natural resources or because of pollution. Mainstream economists, the high priests of secular societies, condemned it fiercely. Their gospel of perpetual economic growth, during which technological progress would solve all problems, promises a bright future for all mankind. On the other hand, engineers, natural scientists, and mathematicians realized that the breakdown scenario is due to the inclusion of the First and the Second Law of Thermodynamics in the Club-of-Rome’s world model. According to these laws, nothing happens in the world without energy conversion and entropy production. In 1865, Rudolph Clausius, the discoverer of entropy, published the laws as the constitution of the universe. Entropy is the physical measure of disorder. Without a proper understanding of energy and entropy in the economy, all efforts to achieve sustainability will fail.

Summary: Britain has been a global leader in reducing emissions, but little progress has been made on heat, which accounts for almost one-third of UK emissions and the largest single share is domestic heat, which is responsible for 17% of the national total. Given the UK’s 2050 “Net-Zero” commitment, decarbonizing heat is becoming urgent and currently one of the main pathways involves its electrification. Here, we present a spatially explicit optimization model that investigates the implications of electrifying domestic heat on the operation of the power sector. Using hourly historical gas demand data, we conclude that the domestic peak heat demand is almost 50% lower than widely cited values. A 100% electrification pathway can be achieved with only a 1.3-fold increase in generation capacity compared to a power-only decarbonization scenario, but only by leveraging the role of thermal energy storage technologies without which a further 40% increase would be needed.

The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease.

Abstract Lack of bone volume to place dental implants is frequently a problem in the reconstruction of edentulous patients. Even though autografts are the gold standard for jaw regeneration, morbidity associated with the harvesting site stimulates the demand for other substitutes. The aim of this study is to characterize the incorporation and the osteogenic ability of a viable cryopreserved human bone graft (VC-HBG) in the mandibular augmentation in rats. Bone chips from fresh human vertebrae cadaveric donors were processed, cryoprotected and deep-frozen at − 80 °C maintaining its cell viability. A jaw augmentation model was used in 20 athymic nude rats allocated into 2 groups to either receive the VC-HBG or an acellular graft as control (A-HBG). The assessment of the grafts' incorporation was performed at 4 and 8 weeks by micro-CT, histomorphometry and immunohistochemistry. Bone volume gain was significantly higher for the VC-HBG group at both time points. At 4 weeks, the A-HBG group presented significantly higher mineral density, but at 8 weeks, the VC-HBG group showed significantly higher values than the A-HBG. There was no statistical difference between VC-HBG and A-HBG groups at 4-weeks for remaining graft particles, while at 8 weeks, the VC-HBG group showed significantly less graft remnants. Collagen I, osteopontin and tartrate-resistant acid phosphatase expression were significantly higher in the VC-HBG group at both time points, while osteocalcin expression was significantly higher in the VC-HBG group at 8-weeks compared to the A-HBG group. This experimental research demonstrated that the VC-HBG shows positive osteogenic properties, greater bone formation, higher rate of bone remodeling and a better overall incorporation in rats' mandibles compared to the A-HBG.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Abstract Non-invasive oxygen saturation (SpO2) is a central vital sign used to shape the management of COVID-19 patients. Yet, there have been no report quantitatively describing SpO2 dynamics and patterns in COVID-19 patients using continuous SpO2 recordings. We performed a retrospective observational analysis of the clinical information and 27 K hours of continuous SpO2 high-resolution (1 Hz) recordings of 367 critical and non-critical COVID-19 patients hospitalised at the Rambam Health Care Campus, Haifa, Israel. An absolute SpO2 threshold of 93% most efficiently discriminated between critical and non-critical patients, regardless of oxygen support. Oximetry-derived digital biomarker (OBMs) computed per 1 h monitoring window showed significant differences between groups, notably the cumulative time below 93% SpO2 (CT93). Patients with CT93 above 60% during the first hour of monitoring, were more likely to require oxygen support. Mechanical ventilation exhibited a strong effect on SpO2 dynamics by significantly reducing the frequency and depth of desaturations. OBMs related to periodicity and hypoxic burden were markedly affected, up to several hours before the initiation of the mechanical ventilation. In summary, OBMs, traditionally used in the field of sleep medicine research, are informative for continuous assessment of disease severity and response to respiratory support of hospitalised COVID-19 patients. In conclusion, OBMs may improve risk stratification and therapy management of critical care patients with respiratory impairment.

In this disease mapping study, the authors estimate disability-adjusted life year rates for three of the major causes of mortality for children under five 43 countries in sub-Saharan Africa. They identify significant heterogeneity at the subnational level, highlighting the need for a targeted intervention approach.

Genetically encoded sensors have been developed and become versatile tools for imaging serotonin dynamics. Here, authors developed a family of serotonin (5-HT) sensors (sDarken), three variants with different affinities for 5-HT enable high spatiotemporal resolution of 5-HT dynamics.

Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.

Abstract Positional plagiocephaly (PP) is the most common skull deformity in infants. Different classification systems exist for graduating the degree of PP, but all of these systems are based on two-dimensional (2D) parameters. This limitation leads to several problems stemming from the fact that 2D parameters are used to classify the three-dimensional (3D) shape of the head. We therefore evaluate existing measurement parameters and validate a newly developed 3D parameter for quantifying PP. Additionally, we present a new classification of PP based on a 3D parameter. 210 patients with PP and 50 patients without PP were included in this study. Existing parameters (2D and 3D) and newly developed volume parameters based on a 3D stereophotogrammetry scan were validated using ROC curves. Additionally, thresholds for the new 3D parameter of a 3D asymmetry index were assessed. The volume parameter 3D asymmetry index quantifies PP equally as well as the gold standard of 30° diagonal difference. Moreover, a 3D asymmetry index allows for a 3D-based classification of PP. The 3D asymmetry index can be used to define the degree of PP. It is easily applicable in stereophotogrammetric datasets and allows for comparability both intra- and inter-individually as well as for scientific analysis.

In this work, the authors determine the crystal structure of a ProQ/FinO RNA chaperone bound to its RNA target. This provides insight into how this family of bacterial proteins recognize transcriptional terminator structures.

Abstract Claudin-3 is a tight junction protein that has often been associated with the progression and metastasis of various tumors. Here, the role of claudin-3 in tumor-induced lymphangiogenesis is investigated. We found an increased lymphangiogenesis in the B16F10 tumor in claudin-3 knockout mice, accompanied by augmented melanoma cell metastasis into sentinel lymph nodes. In vitro, the overexpression of claudin-3 on lymphatic endothelial cells inhibited tube formation by suppressing cell migration, resulting in restricted lymphangiogenesis. Further experiments showed that claudin-3 inhibited lymphatic endothelial cell migration by regulating the PI3K signaling pathway. Interestingly, the expression of claudin-3 in lymphatic endothelial cells is down-regulated by vascular endothelial growth factor C that is often present in the tumor microenvironment. This study indicates that claudin-3 plays an important role as a signaling molecule in lymphatic endothelial cell activity associated with tumor lymphangiogenesis, which may further contribute to melanoma metastasis.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Abstract As an emerging dietary essential fatty acid, pentadecanoic acid (C15:0) is expected to have bioactive metabolites with broad health benefits. Here, we evaluated pentadecanoylcarnitine, an endogenous C15:0 metabolite, for dose dependent cell-based activities, including measurement of its effects on 148 clinically relevant biomarkers across twelve primary human cell systems mimicking various disease states. Mechanisms of action for pentadecanoylcarnitine were also assessed across 78 cell-based target assays. Pentadecanoylcarnitine had dose-dependent anti-inflammatory activities, including lower IL-1α, ITAC, MCP-1, and IP-10, across five cell systems relevant to treating cardiovascular, immune, neoplastic, pulmonary, and skin diseases. Targeted assays showed pentadecanoylcarnitine as a full-acting cannabinoid 1 and 2 receptor agonist (EC50 3.7 and 3.2 µM, 111% and 106% maximum activity compared to the positive control, respectively). Pentadecanoylcarnitine also had 5-HT1A and 5-HT1B receptor agonist and histamine H1 and H2 receptor antagonist activities. In summary, pentadecanoylcarnitine, a second discovered full-acting endocannabinoid, had broad pleiotropic activities relevant to regulating inflammation, pain, mood, and sleep. This study’s findings further the need to evaluate the potential health impacts of C15:0 nutritional deficiencies caused by population-wide avoidance of all dietary saturated fats, including C15:0.

HNRNPU is an RNA splicing protein associated with brain disorders such as early onset seizures. Here they show that HNRNPU functions to maintain neural progenitors and their progeny by regulating splicing of key neuronal genes.

Abstract Alveolar echinococcosis is a rare parasitic disease, most frequently affecting the liver, as a slow-growing tumor-like lesion. If inoperable, long-term benzimidazole therapy is required, which is associated with high healthcare costs and occasionally with increased morbidity. The aim of our study was to determine the role 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in staging of patients with alveolar echinococcosis and to identify quantitative imaging parameters related to patient outcome and/or duration of benzimidazole therapy. In this single-center retrospective cohort study, 47 PET/CT performed for staging in patients with confirmed alveolar echinococcosis were analysed. In 43 patients (91%) benzimidazole therapy was initiated and was successfully stopped after a median of 870 days (766–2517) in 14/43 patients (33%). In inoperable patients, tests for trend of survivor functions displayed clear trends for longer benzimidazole therapy duration (p = 0.05; n = 25), and for longer time intervals to reach non-detectable serum concentration of Em-18 antibodies (p = 0.01, n = 15) across tertiles of SUVratio (maximum standardized uptake value in the echinococcus manifestation compared to normal liver tissue). Hence, in inoperable patients with alveolar echinococcosis, PET/CT performed for staging may predict the duration of benzimidazole therapy.

Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.

Abstract Chromatin organization over multiple length scales plays a critical role in the regulation of transcription. Deciphering the interplay of these processes requires high-resolution, three-dimensional, quantitative imaging of chromatin structure in vitro. Herein, we introduce ChromSTEM, a method that utilizes high-angle annular dark-field imaging and tomography in scanning transmission electron microscopy combined with DNA-specific staining for electron microscopy. We utilized ChromSTEM for an in-depth quantification of 3D chromatin conformation with high spatial resolution and contrast, allowing for characterization of higher-order chromatin structure almost down to the level of the DNA base pair. Employing mass scaling analysis on ChromSTEM mass density tomograms, we observed that chromatin forms spatially well-defined higher-order domains, around 80 nm in radius. Within domains, chromatin exhibits a polymeric fractal-like behavior and a radially decreasing mass-density from the center to the periphery. Unlike other nanoimaging and analysis techniques, we demonstrate that our unique combination of this high-resolution imaging technique with polymer physics-based analysis enables us to (i) investigate the chromatin conformation within packing domains and (ii) quantify statistical descriptors of chromatin structure that are relevant to transcription. We observe that packing domains have heterogeneous morphological properties even within the same cell line, underlying the potential role of statistical chromatin packing in regulating gene expression within eukaryotic nuclei.

Tight junctions are formed by claudin proteins that can be classified as pore- or barrier-forming. Here, Shashikanth et al. report a third function, termed interclaudin interference, in which one claudin inhibits pore function of another claudin by disrupting its polymeric complexes.

The research of polylactic acid (PLA) packaging materials with high degradation rate is important toward high rate biodegradable packaging materials. The samples (PLA-mango seed residue-clays) were evaluated by degradation analysis (in water and in soil) followed by FTIR, NMR, SEM/EDS and Texturometer analysis. The samples degradation was more effective in water than in soil, probably due to a coupled effect of water and microbiological degradation. PLA-kernel-tegument samples degraded more than PLA-kernel samples due to the effectiveness action of kernel and tegument together in the samples’ degradation. PLA-Bofe samples degraded less than PLA-kernel-tegument and PLA-kernel-tegument-Bofe samples, PLA-Chocolate clay (Bofe and Chocolate are organo-montmorillonite clays) samples degraded more than PLA-kernel-tegument-Chocolate samples and less than PLA-kernel-tegument samples, probably due to multiples interaction among the Chocolate clay and mango components. The FTIR bands after samples hydrolytic and soil degradation presented low intensity, probably indicating materials degradation. New bands were observed after soil degradation, most likely related to accumulated soil and band displacement, indicative of samples degradation. The NMR relaxation data confirm the degradation process observed form the other techniques, observing the changes in the values of proton relaxation data for all samples, comparing the values after and before been degraded.

Abstract Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg−1) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10−6 M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10−6 M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO.