Societal Impact Statement Combining natural and social science approaches to conduct archeological research on wooden cultural relics is important for exploring major aspects of ancient... Show moreSocietal Impact Statement Combining natural and social science approaches to conduct archeological research on wooden cultural relics is important for exploring major aspects of ancient civilizations. The Forbidden City in Beijing, China, is the largest existing wooden palace complex in the world. We examined ancient DNA of imperial wood "Nanmu" specimens taken from representative structural components of the Forbidden City, in order to provide a new perspective on the long-standing dispute about its species. This allowed us to accurately identify and properly restore these wooden artifacts and improved our understanding of the past interactions between plant distribution, forest resources, and human activities. Exploring the life styles and production methods of past generations using plant resources can help us to improve our understanding of human civilization. Nanmu, known for its high wood quality, was exclusively used for imperial palace construction in the 15th-19th centuries in China, yet its species has been a subject of long-standing debate. Here, we revisit this unresolved problem, using morphology and ancient DNA (aDNA) to analyze 21 centuries-old Nanmu specimens sampled from representative palaces of the Forbidden City. Cytochemical staining demonstrated that endogenous aDNA sporadically occurs in the wood ray parenchyma cells of Nanmu specimens. High-quality plastid genomes were retrieved from archeological woods for the first time via an aDNA capture method, with 90%-100% coverage (137,663-152,805 bp) and sequence depths of 27.05- to 1409.94-fold. Utilizing these ancient genomes, our results demonstrate that Phoebe zhennan and Phoebe hui are most likely the main species of Nanmu in the Forbidden City. This finding diverges from the prevailing view that Nanmu encompasses woods from the whole genus Phoebe and even its close relative Machilus. It also shows that stringent criteria were used when selecting construction materials for the Forbidden City. By combining morphological traits with aDNA analyses, we provide a new solution for identifying the species of timber used for ancient architecture, and we increase our understanding of the way in which forest resources were recognized and utilized by our ancestors despite the lack of a plant taxonomic framework in ancient times. Show less
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent)... Show moreWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations. Show less
Objective To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-alpha inhibitor therapy in patients with active... Show moreObjective To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-alpha inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).Methods This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.Results The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein <= 3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.Conclusions Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab. Show less
Westhovens, R.; Rigby, W.F.C.; Heijde, D. van der; Ching, D.W.T.; Stohl, W.; Kay, J.; ... ; Burmester, G.R. 2021
Objectives To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure... Show moreObjectives To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure.MethodsThis 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24.ResultsThe primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was -1.0 and -0.94 with FIL200+MTX and FIL100+MTX, respectively, versus -0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments.ConclusionsFIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX. Show less
Lens, F.P.; Liang, C.; Guo, Y.; Tang, X.; Jahanbanifard, M.; Soares Correa da Silva, F.; ... ; Verbeek, F.J. 2020
Wood anatomy is one of the most important methods for timber identification. However, training wood anatomy experts is time-consuming, while at the same time the number of senior wood anatomists... Show moreWood anatomy is one of the most important methods for timber identification. However, training wood anatomy experts is time-consuming, while at the same time the number of senior wood anatomists with broad taxonomic expertise is de- clining. Therefore, we want to explore how a more automated, computer-assisted approach can support accurate wood identification based on microscopic wood anatomy. For our exploratory research, we used an available image dataset that has been applied in several computer vision studies, consisting of 112 — mainly neotropical — tree species representing 20 images of transverse sections for each species. Our study aims to review existing computer vision methods and compare the success of species identification based on (1) several image classifiers based on manually adjusted texture features, and (2) a state-of-the-art approach for image classification based on deep learning, more specifically Convolutional Neural Networks (CNNs). In support of previous studies, a considerable increase of the correct identification is accomplished using deep learning, leading to an accuracy rate up to 95.6%. This remarkably high success rate highlights the fundamental potential of wood anatomy in species identification and motivates us to expand the existing database to an extensive, worldwide reference database with transverse and tangential microscopic images from the most traded timber species and their look-a-likes. This global reference database could serve as a valuable future tool for stakeholders involved in combatting illegal logging and would boost the societal value of wood anatomy along with its collections and experts. Show less
Purpose Cardiac motion tracking enables quantitative evaluation of myocardial strain, which is clinically interesting in cardiovascular disease research. However, motion tracking is difficult to... Show morePurpose Cardiac motion tracking enables quantitative evaluation of myocardial strain, which is clinically interesting in cardiovascular disease research. However, motion tracking is difficult to perform manually. In this paper, we aim to develop and compare two fully automated motion tracking methods for the steady state free precession (SSFP) cine magnetic resonance imaging (MRI), and explore their use in real clinical scenario with different patient groups. Methods We proposed two automated cardiac motion tracking method: (a) a traditional registration-based method, named full cardiac cycle registration, which simultaneously tracks all cine frames within a full cardiac cycle by joint registration of all frames; and (b) a modern convolutional neural network (CNN)-based method, named Groupwise MotionNet, which enhances the temporal coherence by fusing motion along a continuous time scale. Both methods were evaluated on the healthy volunteer data from the MICCAI 2011 STACOM Challenge, as well as on patient data including hypertrophic cardiomyopathy (HCM) and myocardial infarction (MI). Results The full cardiac cycle registration method achieved an average end-point error (EPE) 2.89 +/- 1.57 mm for cardiac motion tracking, with computation time of around 9 min per short-axis cine MRI (size 128 x 128, 30 cardiac phases). In comparison, the Groupwise MotionNet achieved an average EPE of 0.94 +/- 1.59 mm, taking < 1 s for a full cardiac phases. Further experiments showed that registration method had stable performance, independent of patient cohort and MRI machine, while the CNN-based method relied on the training data to deliver consistently accurate results. Conclusion Both registration-based and CNN-based method can track the cardiac motion from SSFP cine MRI in a fully automated manner, while taking temporal coherence into account. The registration method is generic, robust, but relatively slow; the CNN-based method trained with heterogeneous data was able to achieve high tracking accuracy with real-time performance. Show less
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear,... Show moreIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding. Show less
In numerous multimedia and multi-modal tasks from image and video retrieval to zero-shot recognition to multimedia question and answering, bridging image and text representations plays an... Show moreIn numerous multimedia and multi-modal tasks from image and video retrieval to zero-shot recognition to multimedia question and answering, bridging image and text representations plays an important and in some cases an indispensable role. To narrow the modality gap between vision and language, prior approaches attempt to discover their correlated semantics in a common feature space. However, these approaches omit the intra-modal semantic consistency when learning the inter-modal correlations. To address this problem, we propose cycle-consistent embeddings in a deep neural network for matching visual and textual representations. Our approach named as CycleMatch can maintain both inter-modal correlations and intra-modal consistency by cascading dual mappings and reconstructed mappings in a cyclic fashion. Moreover, in order to achieve a robust inference, we propose to employ two late-fusion approaches: average fusion and adaptive fusion. Both of them can effectively integrate the matching scores of different embedding features, without increasing the network complexity and training time. In the experiments on cross-modal retrieval, we demonstrate comprehensive results to verify the effectiveness of the proposed approach. Our approach achieves state-of-the-art performance on two well-known multi-modal datasets, Flickr30K and MSCOCO. Show less
Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans1,2. Most humans have antibodies against S. aureus, but these are... Show moreMethicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans1,2. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients3. Previous vaccine development programs have not been successful4. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc)5,6. It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS7, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5–40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences. Show less
