Explore the vast range of titles available.

The giant sequoia (Sequoiadendron giganteum) of California are massive, long-lived trees that grow along the U.S. Sierra Nevada mountains. Genomic data are limited in giant sequoia and producing a reference genome sequence has been an important goal to allow marker development for restoration and management. Using deep-coverage Illumina and Oxford Nanopore sequencing, combined with Dovetail chromosome conformation capture libraries, the genome was assembled into eleven chromosome-scale scaffolds containing 8.125 Gbp of sequence. Iso-Seq transcripts, assembled from three distinct tissues, was used as evidence to annotate a total of 41,632 protein-coding genes. The genome was found to contain, distributed unevenly across all 11 chromosomes and in 63 orthogroups, over 900 complete or partial predicted NLR genes, of which 375 are supported by annotation derived from protein evidence and gene modeling. This giant sequoia reference genome sequence represents the first genome sequenced in the Cupressaceae family, and lays a foundation for using genomic tools to aid in giant sequoia conservation and management.

Background The CyberKnife Xsight lung-tracking system (XLTS) provides an alternative to fiducial-based target-tracking systems (FTTS) for non-small-cell lung cancer (NSCLC) patients without invasive fiducial insertion procedures. This study provides a method for 3D independent dosimetric verification of the accuracy of the FTTS compared to the XLTS without relying on log-files generated by the CyberKnife system. Methods A respiratory motion trace was taken from a 4D-CT of a real lung cancer patient and applied to a modified QUASAR™ respiratory motion phantom. A novel approach to 3D dosimetry was developed using Gafchromic EBT3 film, allowing the 3D dose distribution delivered to the moving phantom to be reconstructed. Treatments were planned using the recommended margins for one and three fiducial markers and XLTS 2-view, 1-view and 0-view target-tracking modalities. The dose delivery accuracy was analysed by comparing the reconstructed dose distributions to the planned dose distributions using gamma index analysis. Results For the 3%/2 mm gamma criterion, gamma passing rates up to 99.37% were observed for the static deliveries. The 3-fiducial and 1-fiducial-based deliveries exhibited passing rates of 93.74% and 97.82%, respectively, in the absence of target rotation. When target rotation was considered, the passing rate for 1-fiducial tracking degraded to 91.24%. The passing rates observed for XLTS 2-view, 1-view and 0-view target-tracking were 92.78%, 96.22% and 76.08%, respectively. Conclusions Except for the XLTS 0-view, the dosimetric accuracy of the XLTS was comparable to the FTTS under equivalent treatment conditions. This study gives us further confidence in the CyberKnife XLTS and FTTS systems.

Sequencing, assembly, and annotation of the 26.5 Gbp hexaploid genome of coast redwood (Sequoia sempervirens) was completed leading toward discovery of genes related to climate adaptation and investigation of the origin of the hexaploid genome. Deep-coverage short-read Illumina sequencing data from haploid tissue from a single seed were combined with long-read Oxford Nanopore Technologies sequencing data from diploid needle tissue to create an initial assembly, which was then scaffolded using proximity ligation data to produce a highly contiguous final assembly, SESE 2.1, with a scaffold N50 size of 44.9 Mbp. The assembly included several scaffolds that span entire chromosome arms, confirmed by the presence of telomere and centromere sequences on the ends of the scaffolds. The structural annotation produced 118,906 genes with 113 containing introns that exceed 500 Kbp in length and one reaching 2 Mb. Nearly 19 Gbp of the genome represented repetitive content with the vast majority characterized as long terminal repeats, with a 2.9:1 ratio of Copia to Gypsy elements that may aid in gene expression control. Comparison of coast redwood to other conifers revealed species-specific expansions for a plethora of abiotic and biotic stress response genes, including those involved in fungal disease resistance, detoxification, and physical injury/structural remodeling and others supporting flavonoid biosynthesis. Analysis of multiple genes that exist in triplicate in coast redwood but only once in its diploid relative, giant sequoia, supports a previous hypothesis that the hexaploidy is the result of autopolyploidy rather than any hybridizations with separate but closely related conifer species.

Abstract Abundance of established polyploid lineages varies across lineages, evolutionary time, and geography, suggesting both genetics and environment play a role in polyploid persistence. We show Arabidopsis lyrata is the most polyploid-rich species complex in the Arabidopsis genus, with multiple origins of autotetraploidy. This is revealed by genomic data from over 400 A. lyrata samples across Eurasia. We found over 30 previously undescribed autotetraploid populations in Siberia with a minimum of two separate origins, independent of those previously reported in Central Europe. The establishment of Siberian tetraploids is mediated by meiotic adaptation at the same genes as in European tetraploid A. lyrata and Arabidopsis arenosa, despite their genomic divergence and geographical separation. Haplotype analysis based on synthetic long-read assemblies supports the long-range introgression of adaptive alleles from the tetraploid interspecific pool of European A. lyrata and A. arenosa to tetraploid Siberian A. lyrata. Once adaptations to polyploidy emerge, they promote the establishment of new polyploid lineages through adaptive inter- and intraspecific introgression.

Abundance of polyploidy varies across lineages, evolutionary time and geography, suggesting both genetics and environment play a role in polyploid persistence. Arabidopsis lyrata appears to be the most polyploidy-rich species-complex in the Arabidopsis genus, with multiple origins of autotetraploidy. This is revealed by genomic data from over 400 samples across Eurasia. We found over 30 previously undescribed autotetraploid populations in Siberia with a minimum of two separate origins, independent of those previously reported in Central Europe. The establishment of Siberian tetraploids is mediated by meiotic adaptation at the same genes as in European tetraploid A. lyrata and Arabidopsis arenosa, despite high divergence and geographical separation. Haplotype analysis based on synthetic long-read assemblies supports the long-range introgression of adaptive alleles from the tetraploid interspecific pool of European A. lyrata and A. arenosa to tetraploid Siberian A. lyrata. Once evolved, adaptation to polyploidy promotes the establishment of new polyploid lineages through adaptive inter– and intraspecific introgression.

The giant sequoia Sequoiadendron giganteum of California are massive, long-lived trees that grow along the U.S. Sierra Nevada mountains. As they grow primarily in isolated groves within a narrow range, conservation of existing trees has been a national goal for over 150 years. Genomic data are limited in giant sequoia, and the assembly and annotation of the first giant sequoia genome has been an important goal to allow marker development for restoration and management. Using Illumina and Oxford Nanopore sequencing combined with Dovetail chromosome conformation capture libraries, 8.125 Gbp of sequence was assembled into eleven chromosome-scale scaffolds. This giant sequoia assembly represents the first genome sequenced in the Cupressaceae family, and lays a foundation for using genomic tools to aid in giant sequoia conservation and management. Beyond conservation and management applications, the giant sequoia assembly is a resource for answering questions about the life history of this enigmatic and robust species. Here we provide an example by taking an inventory of the large and complex family of NLR type disease resistance genes.

Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Dengue viruses (DENV) are the causative agents of dengue, the world's most prevalent arthropod-borne disease with around 40% of the world's population at risk of infection annually. Wolbachia pipientis, an obligate intracellular bacterium, is being developed as a biocontrol strategy against dengue because it limits replication of the virus in the mosquito. The Wolbachia strain wMel, which has been introduced into the mosquito vector, Aedes aegypti, has been shown to invade and spread to near fixation in field releases. Standard measures of Wolbachia's efficacy for blocking virus replication focus on the detection and quantification of virus in mosquito tissues. Examining the saliva provides a more accurate measure of transmission potential and can reveal the extrinsic incubation period (EIP), that is, the time it takes virus to arrive in the saliva following the consumption of DENV viremic blood. EIP is a key determinant of a mosquito's ability to transmit DENVs, as the earlier the virus appears in the saliva the more opportunities the mosquito will have to infect humans on subsequent bites. We used a non-destructive assay to repeatedly quantify DENV in saliva from wMel-infected and Wolbachia-free wild-type control mosquitoes following the consumption of a DENV-infected blood meal. We show that wMel lengthens the EIP, reduces the frequency at which the virus is expectorated and decreases the dengue copy number in mosquito saliva as compared to wild-type mosquitoes. These observations can at least be partially explained by an overall reduction in saliva produced by wMel mosquitoes. More generally, we found that the concentration of DENV in a blood meal is a determinant of the length of EIP, saliva virus titer and mosquito survival. The saliva-based traits reported here offer more disease-relevant measures of Wolbachia's effects on the vector and the virus. The lengthening of EIP highlights another means, in addition to the reduction of infection frequencies and DENV titers in mosquitoes, by which Wolbachia should operate to reduce DENV transmission in the field.

Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT. PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m2 and intravenous cyclophosphamide 300 mg/m2 daily for 3 days) followed 2–7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8+ and CD4+ CAR+ T cells for a total target dose of 100 × 106 CAR+ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103. Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70–78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1–18·0). 49 (80% [95% CI 68–89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths. These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended. Juno Therapeutics, a Bristol-Myers Squibb company.