ALBERT

Description: 〈p〉 A nearly 20-year hiatus in major seismic activity in southern California ended on 4 July 2019 with a sequence of intersecting earthquakes near the city of Ridgecrest, California. This sequence included a foreshock with a moment magnitude (〈i〉M〈/i〉〈sub〉w〈/sub〉) of 6.4 followed by a 〈i〉M〈/i〉〈sub〉w〈/sub〉 7.1 mainshock nearly 34 hours later. Geodetic, seismic, and seismicity data provided an integrative view of this sequence, which ruptured an unmapped multiscale network of interlaced orthogonal faults. This complex fault geometry persists over the entire seismogenic depth range. The rupture of the mainshock terminated only a few kilometers from the major regional Garlock fault, triggering shallow creep and a substantial earthquake swarm. The repeated occurrence of multifault ruptures, as revealed by modern instrumentation and analysis techniques, poses a formidable challenge in quantifying regional seismic hazards.〈/p〉

Description: 〈span〉〈div〉Summary〈/div〉We propose a new Bayesian method to reveal the 〈span〉Vs〈/span〉 structure of the near surface of the earth using spatial autocorrelation (SPAC) functions and apply this new method to synthetic, broadband, and geophone datasets. The principle of SPAC is introduced, and an implementation of the Bayesian Monte Carlo inversion (BMCI) for modeling SPAC coherency functions is described. To demonstrate its effectiveness, BMCI is applied to synthetic tests, data from 14 SPAC array sites in the Salt Lake Valley (SLV), Utah, and two arrays (one broadband and one geophone) located in south central Utah. The 〈span〉Vs〈/span〉 models derived from previous SPAC analysis of the 14 SLV sites differ by 10 per cent at most from those determined by BMCI and lie within uncertainties determined for the BMCI models. These agreements demonstrate the effectiveness of the BMCI method. The synthetic tests and applications to the SLV SPAC data show BMCI has great potential to resolve 〈span〉Vs〈/span〉 structure down to at least 400 m. To achieve resolution for deeper 〈span〉Vs〈/span〉 structure, longer duration deployments, wider array apertures, and additional seismometers or geophones can be employed. Additionally, when the target frequencies are greater than 0.1 Hz, there is no apparent disadvantage in using geophone data for BMCI compared to broadband data. Most significantly, BMCI places a quantifiable constraint on the uncertainties of the 〈span〉Vs〈/span〉 models as well as 〈span〉Vs30〈/span〉.〈/span〉

Description: 〈span〉〈div〉SUMMARY〈/div〉Recently an ambitious experiment combining deep seismic surveys from near-vertical and wide-angle acquisition methods was carried out in Brazil. The seismic lines are essentially coincident and crossed the Parnaíba Basin from west to east near latitude 5°S. Here, the wide-angle reflection and refraction (WARR) and deep seismic reflection (DSR) results, which were previously interpreted independently, are compared by directly correlating WARR interfaces converted to TWTT with the major reflective horizons identified in the zero-offset image and by considering coincident reflectivity patterns displayed in both data sets. This integrated WARR and DSR analysis allowed a spatial association of the apparently acoustically featureless crust imaged in the DSR profile to the high reflectivity observed in the WARR data. Numerical tests and elastic modelling show that variations of the elastic properties of the crust, particularly as they are characterized by low 〈span〉Vp〈/span〉 and 〈span〉Vs〈/span〉 contrasts with a possible increase of the 〈span〉Vp〈/span〉/〈span〉Vs〈/span〉 ratio, can only weakly explain the observed reflectivity patterns but that fine-scale lithological heterogeneity within the crust is capable of replicating the observed contrasting seismic responses. The segment of the Parnaíba Basin crust that is characterized by fine-scale lithological heterogeneity lies directly above a mafic crustal underplate defined by the WARR model and was named as the Grajaú domain on the basis of WARR-derived velocity model. The applied methodologies allow added value to be taken from the independent seismic data sets and provide new information about crustal structure that may have important implications for overlying intracontinental basin evolution.〈/span〉

Description: 〈p〉To date, sea slugs have been considered the only animals known to sequester functional algal plastids into their own cells, via a process called "kleptoplasty." We report here, however, that endosymbionts in the marine flatworms 〈i〉Baicalellia solaris〈/i〉 and 〈i〉Pogaina paranygulgus〈/i〉 are isolated plastids stolen from diatoms. Ultrastructural data show that kleptoplasts are located within flatworm cells, while algal nuclei and other organelles are absent. Transcriptomic analysis and 〈i〉rbcL〈/i〉 amplicons confirm the absence of algal nuclear mRNA and reveal that the plastids originate from different species of diatoms. Laboratory experiments demonstrated photosynthetic activity and short-term retention of kleptoplasts in starved worms. This lineage of flatworms represents the first known case of functional kleptoplasty involving diatoms and only the second known case of kleptoplasty across the entire tree of animals.〈/p〉

Description: 〈p〉Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.〈/p〉

Description: 〈span〉〈div〉Summary〈/div〉Recently an ambitious experiment combining deep seismic surveys from near-vertical and wide-angle acquisition methods was carried out in Brazil. The seismic lines are essentially coincident and crossed the Parnaíba Basin from west to east near latitude 5° S. Here, the wide-angle reflection and refraction (WARR) and deep seismic reflection (DSR) results, which were previously interpreted independently, are compared by directly correlating WARR interfaces converted to TWTT with the major reflective horizons identified in the zero-offset image and by considering coincident reflectivity patterns displayed in both data sets. This integrated WARR and DSR analysis allowed a spatial association of the apparently acoustically featureless crust imaged in the DSR profile to the high reflectivity observed in the WARR data. Numerical tests and elastic modelling show that variations of the elastic properties of the crust, particularly as they are characterised by low 〈span〉V〈/span〉p and 〈span〉V〈/span〉s contrasts with a possible increase of the 〈span〉V〈/span〉p/〈span〉V〈/span〉s ratio, can only weakly explain the observed reflectivity patterns but that fine-scale lithological heterogeneity within the crust is capable of replicating the observed contrasting seismic responses. The segment of the Parnaíba Basin crust that is characterised by fine-scale lithological heterogeneity lies directly above a mafic crustal underplate defined by the WARR model and was named as the Grajaú domain on the basis of WARR-derived velocity model. The applied methodologies allow added value to be taken from the independent seismic datasets and provide new information about crustal structure that may have important implications for overlying intracontinental basin evolution.〈/span〉

Description: Introduction Malignancy can be heralded by unprovoked venous thromboembolism (VTE) but also by arterial thrombosis. To date it is unknown whether this association is present also in myeloproliferative neoplasms (MPN), in which arterial thrombosis is more frequent that venous thrombosis and solid tumors are reported with an increased frequency. The MPN-K nested case-control study addressed the impact of cytoreductive drugs on the risk of developing second cancer in MPN patients (Barbui T et al, Leukemia 2019); here we re-examined the study database to evaluate the frequency and type of vascular complications in MPN patients with second cancer excluding leukemia and to establish whether arterial and venous thrombosis during follow-up after diagnosis of MPN could predict the occurrence of a second cancer. Patients and methods Cases were patients with second cancer diagnosed concurrently or subsequent to the diagnosis of MPN. Controls were MPN patients without second cancer. For each case with second cancer, up to 3 cancer-free controls were matched by each center for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. Each set consisting of one case and their matched-controls had a similar observational period (from MPN diagnosis until the index date of diagnosis for the second cancer). The study included 647 cases with second cancer (carcinoma, non-melanoma-skin cancers, hematological secondary cancer and melanoma). The most frequent category was carcinoma (n=426, 65.8%). Cases were comparable with the 1,234 matched controls for demographics, type of MPN, and exposure to potential confounders such as mutational profile, abnormal karyotype and cardiovascular risk factors. The thrombotic events of interest were ischemic stroke, transient ischemic attacks, acute coronary syndromes, peripheral arterial thrombosis, deep venous thrombosis (including thrombosis of cerebral and splanchnic veins) and pulmonary embolism. Thrombosis had to be concurrent with or in the 2 years before MPN diagnosis or occurring after MPN diagnosis. The cumulative incidence of either arterial or venous thrombosis from MPN diagnosis was estimated by the Kaplan-Meier method and was compared between cases and controls using the log-rank test. A conditional logistic regression model estimated the Odds Ratio (OR) with 95% Confidence Interval (CI) of second cancer associated with the occurrence of thrombosis before/at diagnosis of MPN and during follow-up. Other covariates were patient age, cardiovascular risk factors, the JAK2V617F mutation, and treatment during follow-up. Results Approximately 20% of either MPN cases or controls had thrombosis before MPN or at diagnosis (19.8% vs. 21.1%, respectively, p=0.462). After a median observation time from diagnosis of MPN to an index date of 4.5 years (interquartile range 1.5-8.2) in cases and 3.7 years (interquartile range 1.5-7.5) in controls, cases showed a percentage of thrombosis higher than in controls (75/647, 11.6% vs. 100/1234, 8.1%, respectively, p=0.013). Approximately one-third of thrombosis preceding cancer occurred in the 12 months before the diagnosis of second cancer (22/75, 29.3%). The excess of thrombosis in cases was due to a higher frequency of arterial thrombosis (6.2% vs. 3.7%, p=0.015), whereas no significant difference was found for venous thrombosis (5.4% vs. 4.3%, p=0.277). While the cumulative incidence of venous thrombosis over time was similar among cases and controls (p=0.864), the cumulative incidence of arterial thrombosis was higher in cases with second cancer (p=0.006) (Figure 1). The excess of arterial thrombosis after MPN diagnosis was limited to cases with carcinoma (6.8% vs 3.9%, p=0.027). In a multivariable model, arterial thrombosis during the follow-up was confirmed to be an independent predictor factor for carcinoma, with an odds ratio of 1.97 (95%CI 1.14-3.41, p=0.015). Conclusions. These findings reveal an association of arterial thrombosis with subsequent second cancer (namely carcinoma) in MPN patients. A possible biological plausibility for this link may be related to an underlying common pathogenic mechanism such as an aberrant inflammatory response consistently found in MPN. This observation may have practical implications and suggests careful clinical surveillance for early diagnosis of second cancer in MPN patients with arterial thrombosis during the follow-up. Disclosures Palandri: Novartis: Consultancy, Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Bonifacio:Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Rumi:novartis: Honoraria, Research Funding. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. McMullin:Italopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Description: Motivation Understanding the protein structural context and patterning on proteins of genomic variants can help to separate benign from pathogenic variants and reveal molecular consequences. However, mapping genomic coordinates to protein structures is non-trivial, complicated by alternative splicing and transcript evidence. Results Here we present VarMap, a web tool for mapping a list of chromosome coordinates to canonical UniProt sequences and associated protein 3D structures, including validation checks, and annotating them with structural information. Availability and implementation https://www.ebi.ac.uk/thornton-srv/databases/VarMap. Supplementary information Supplementary data are available at Bioinformatics online.

Description: DLCBL has recently been classified into genetically defined subtypes based on groupings of particular genetic lesions (Chapuy et al, Nat Med 2018; Schmitz et al, NEJM 2018). One predominant cluster, C3 or EZB, is defined by mutations in the chromatin modifying genes EZH2, KMT2D, and CREBBP as well as alterations in BCL2 including mutations and/or translocation of BCL2 to the IgH enhancer. Since tumors in this cluster are likely dependent on both EZH2 and BCL2, and these oncogenes carry out their effects through distinct mechanisms and pathways, targeting both of these oncogenes is a rational therapeutic approach. We hypothesized that EZH2 inhibition and BCL2 inhibition would be synergistic in DLBCL with characteristics of the C3/EZB cluster. To test this, we evaluated the EZH2 inhibitor tazemetostat and the BCL2 inhibitor venetoclax in DLBCL cells, 3D lymphoma organoids, and patient derived xenografts. To assess the effect of combination therapy with tazemetostat and venetoclax, we administered each drug alone and the combination in a panel of DLBCL cell lines, including cells with and without EZH2 mutation and BCL2 translocation. In DLBCL cells with both a BCL2 translocation and EZH2 mutation, the combination resulted in increased killing compared to either drug alone (Figure 1, SUDHL6 (p