颂扬牺牲是危机时代女性解放议程中必然的一部分。尽管如此,作为传统中国"列女传"的一脉,女性牺牲者进入男性荣誉的烈士谱系并非名正言顺。看似悖谬的是,现代第一女烈士秋瑾在革命告成之前因为是"女性"被排除在外,革命胜利之后又因为是"女性"而备受优待。女性进入烈士谱系是一个神圣化的过程,也是一个去性别化的过程。在文学史的意义上,丁玲的"准烈士"小说不仅颠覆了传统文学节妇烈女的叙事模式,而且打破了烈士文章过度颂扬的刻板程式。 <<<

Xingyao Xiong, Junbo Gou, Qinggang Liao, Yanlin Li, Qian Zhou, Guiqi Bi, Chong Li, Ran Du, Xiaotong Wang, Tianshu Sun, Lvjun Guo, Haifei Liang, Pengjun Lu, Yaoyao Wu, Zhonghua Zhang, Dae-Kyun Ro, Yi Shang, Sanwen Huang, Jianbin Yan <<<

The ancient gymnosperm genus Taxus is the exclusive source of the anticancer drug paclitaxel, yet no reference genome sequences are available for comprehensively elucidating the paclitaxel biosynthesis pathway. We have completed a chromosome-level genome of Taxus chinensis var. mairei with a total length of 10.23 gigabases. Taxus shared an ancestral whole-genome duplication with the coniferophyte lineage and underwent distinct transposon evolution. We discovered a unique physical and functional grouping of CYP725As (cytochrome P450) in the Taxus genome for paclitaxel biosynthesis. We also identified a gene cluster for taxadiene biosynthesis, which was formed mainly by gene duplications. This study will facilitate the elucidation of paclitaxel biosynthesis and unleash the biotechnological potential of Taxus. <<<

The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy. <<<

Genome-wide association studies (GWAS) test hundreds of thousands of genetic variants across many genomes to find those statistically associated with a specific trait or disease. This methodology has generated a myriad of robust associations for a range of traits and diseases, and the number of associated variants is expected to grow steadily as GWAS sample sizes increase. GWAS results have a range of applications, such as gaining insight into a phenotype’s underlying biology, estimating its heritability, calculating genetic correlations, making clinical risk predictions, informing drug development programmes and inferring potential causal relationships between risk factors and health outcomes. In this Primer, we provide the reader with an introduction to GWAS, explaining their statistical basis and how they are conducted, describe state-of-the art approaches and discuss limitations and challenges, concluding with an overview of the current and future applications for GWAS results. <<<

MRI provides a powerful tool for studying the functional and structural connections in the brain non-invasively. The technique of functional connectivity (FC) exploits the intrinsic temporal correlations of slow spontaneous signal fluctuations to characterise brain functional networks. In addition, diffusion MRI fibre-tracking can be used to study the white matter structural connections. In recent years, there has been considerable interest in combining these two techniques to provide an overall structural-functional description of the brain. In this work we applied the recently proposed super-resolution track-weighted imaging (TWI) methodology to demonstrate how whole-brain fibre-tracking data can be combined with FC data to generate a track-weighted (TW) FC map of FC networks. The method was applied to data from 8 healthy volunteers, and illustrated with (i) FC networks obtained using a seeded connectivity-based analysis (seeding in the precuneus/posterior cingulate cortex, PCC, known to be part of the default mode network), and (ii) with FC networks generated using independent component analysis (in particular, the default mode, attention, visual, and sensory-motor networks). TW-FC maps showed high intensity in white matter structures connecting the nodes of the FC networks. For example, the cingulum bundles show the strongest TW-FC values in the PCC seeded-based analysis, due to their major role in the connection between medial frontal cortex and precuneus/posterior cingulate cortex; similarly the superior longitudinal fasciculus was well represented in the attention network, the optic radiations in the visual network, and the corticospinal tract and corpus callosum in the sensory-motor network. The TW-FC maps highlight the white matter connections associated with a given FC network, and their intensity in a given voxel reflects the functional connectivity of the part of the nodes of the network linked by the structural connections traversing that voxel. They therefore contain a different (and novel) image contrast from that of the images used to generate them. The results shown in this study illustrate the potential of the TW-FC approach for the fusion of structural and functional data into a single quantitative image. This technique could therefore have important applications in neuroscience and neurology, such as for voxel-based comparison studies. <<<

We propose a novel method for unsupervised image-to-image translation, which incorporates a new attention module and a new learnable normalization function in an end-to-end manner. The attention module guides our model to focus on more important regions distinguishing between source and target domains based on the attention map obtained by the auxiliary classifier. Unlike previous attention-based method which cannot handle the geometric changes between domains, our model can translate both images requiring holistic changes and images requiring large shape changes. Moreover, our new AdaLIN (Adaptive Layer-Instance Normalization) function helps our attention-guided model to flexibly control the amount of change in shape and texture by learned parameters depending on datasets. Experimental results show the superiority of the proposed method compared to the existing state-of-the-art models with a fixed network architecture and hyper-parameters. Our code and datasets are available at this https URL or this https URL. <<<

Previous studies have identified neurons in the postsubiculum which discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the environment. Anatomical studies have shown that the postsubiculum contains reciprocal connections with the anterior thalamic nuclei (ATN). In order to determine how the head direction (HD) cell signal is processed in the brain, single- unit recordings were monitored in the ATN of freely moving rats in order to characterize their behavioral and spatial correlates. Animals were trained to retrieve food pellets thrown randomly into a cylindrical apparatus containing a single orientation cue. Single unit recordings in the ATN showed that approximately 60% of the recorded cells discharged in relation to the animal's head direction in the horizontal plane. Observation of the animal and quantitative analyses showed that HD cell firing was not dependent on the animal's behavior, trunk position, linear speed, angular head velocity, or location in the environment. Most of these cells were localized to the anterior dorsal thalamic nucleus. Each HD cell contained only one head direction at which the cell discharged maximally and the firing rate decreased linearly away from this preferred direction. The preferred firing directions from all cells recorded were distributed over a 360° range. Quantitative analysis showed that these cells contained similar discharge parameters (peak firing rate, directional firing range) to values reported previously for post-subicular HD cells (Taube et el., 1990a). Experiments involving rotation of the orientation cue showed that the preferred firing direction could be controlled by a salient visual cue. In contrast to postsubicular HD cells, passive rotation of a restrained animal showed that most ATN HD cells ceased discharging when the animal's head was oriented in the preferred direction. These findings demonstrate the presence of HD cells in the ATN and indicate the potential importance of this area for spatial navigation. The origin of the head direction signal is discussed and it is concluded that because of the presence of reciprocal connections between the postsubiculum and the ATN, further studies are required in order to determine the direction in which this head-directional information is flowing. Finally, ATN HD cells differ from postsubicular HD cells by appearing to require volitional motoric input. <<<

Teri A Manolio, Francis S Collins, Nancy J Cox, David B Goldstein, Lucia A Hindorff, David J Hunter, Mark I McCarthy, Erin M Ramos, Lon R Cardon, Aravinda Chakravarti, Judy H Cho, Alan E Guttmacher, Augustine Kong, Leonid Kruglyak, Elaine Mardis, Charles N Rotimi, Montgomery Slatkin, David Valle, Alice S Whittemore, Michael Boehnke, Andrew G Clark, Evan E Eichler, Greg Gibson, Jonathan L Haines, Trudy F C Mackay, Steven A McCarroll, Peter M Visscher <<<

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment. <<<

The paradigm of surface-expressed programmed death ligand 1 (PDL1) signalling to immune cell programmed death 1 (PD1) to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent. These insights demonstrate that the prevailing cell-extrinsic PDL1 signalling paradigm is useful, but incomplete in important respects. This Perspective discusses historical and recent advances in understanding cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as reliable treatment response biomarkers. Cancer cell-intrinsic PD1 signals and cell-intrinsic PDL1 signals in non-cancer cells are discussed briefly, as are PDL1 signals from soluble and vesicle-bound PDL1 and PDL1 isoforms. We conclude with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field. <<<

Despite over a century of research on intelligence, the cognitive processes underlying intelligent behavior are still unclear. In this review, we summarize empirical results investigating the contribution of cognitive processes associated with working memory capacity, processing speed, and executive processes to intelligence differences. Specifically, we (a) evaluate how cognitive processes associated with the three different cognitive domains have been measured, and (b) how these processes are related to individual differences in intelligence. Consistently, this review illustrates that isolating single cognitive processes using average performance in cognitive tasks is hardly possible. Instead, formal models that implement theories of cognitive processes underlying performance in different cognitive tasks may provide more adequate indicators of single cognitive processes. Therefore, we outlined which models for working memory capacity, processing speed, and executive processes may provide more specific insights into cognitive processes associated with individual differences in intelligence. Finally, we discuss implications of a process-oriented intelligence research using cognitive measurement models for psychometric theories of intelligence and argue that a model-based approach might overcome validity problems of traditional intelligence theories. <<<

Affine registration is indispensable in a comprehensive medical image registration pipeline. However, only a few studies focus on fast and robust affine registration algorithms. Most of these studies utilize convolutional neural networks (CNNs) to learn joint affine and non-parametric registration, while the standalone performance of the affine subnetwork is less explored. Moreover, existing CNN-based affine registration approaches focus either on the local misalignment or the global orientation and position of the input to predict the affine transformation matrix, which are sensitive to spatial initialization and exhibit limited generalizability apart from the training dataset. In this paper, we present a fast and robust learning-based algorithm, Coarse-to-Fine Vision Transformer (C2FViT), for 3D affine medical image registration. Our method naturally leverages the global connectivity and locality of the convolutional vision transformer and the multi-resolution strategy to learn the global affine registration. We evaluate our method on 3D brain atlas registration and template-matching normalization. Comprehensive results demonstrate that our method is superior to the existing CNNs-based affine registration methods in terms of registration accuracy, robustness and generalizability while preserving the runtime advantage of the learning-based methods. The source code is available at this https URL. <<<

Vaccines are one of the greatest successes of public health, preventing millions of cases of disease and death in children each year. However, the efficacy of many vaccines can vary greatly between infants from geographically and socioeconomically distinct locations. Differences in the composition of the intestinal microbiome have emerged as one of the main factors that can account for variations in immunisation outcomes. In this Review, we assess the influence of the gut microbiota upon early life immunity, focusing on two important members of the microbiota with health-promoting and immunomodulatory properties: Bifidobacterium and Bacteroides. Additionally, we discuss their immune stimulatory microbial properties, interactions with the host, and their effect on vaccine responses and efficacy in infants. We also provide an overview of current microbiota-based approaches to enhance vaccine outcomes, and describe novel microbe-derived components that could lead to safer, more effective vaccines and vaccine adjuvants. <<<

Sjors G J G In 't Veld, Mohammad Arkani, Edward Post, Mafalda Antunes-Ferreira, Silvia D'Ambrosi, Daan C L Vessies, Lisa Vermunt, Adrienne Vancura, Mirte Muller, Anna-Larissa N Niemeijer, Jihane Tannous, Laura L Meijer, Tessa Y S Le Large, Giulia Mantini, Niels E Wondergem, Kimberley M Heinhuis, Sandra van Wilpe, A Josien Smits, Esther E E Drees, Eva Roos, Cyra E Leurs, Lee-Ann Tjon Kon Fat, Ewoud J van der Lelij, Govert Dwarshuis, Maarten J Kamphuis, Lisanne E Visser, Romee Harting, Annemijn Gregory, Markus W Schweiger, Laurine E Wedekind, Jip Ramaker, Kenn Zwaan, Heleen Verschueren, Idris Bahce, Adrianus J de Langen, Egbert F Smit, Michel M van den Heuvel, Koen J Hartemink, Marijke J E Kuijpers, Mirjam G A Oude Egbrink, Arjan W Griffioen, Rafael Rossel, T Jeroen N Hiltermann, Elizabeth Lee-Lewandrowski, Kent B Lewandrowski, Philip C De Witt Hamer, Mathilde Kouwenhoven, Jaap C Reijneveld, William P J Leenders, Ann Hoeben, Irma M Verdonck-de Leeuw, C René Leemans, Robert J Baatenburg de Jong, Chris H J Terhaard, Robert P Takes, Johannes A Langendijk, Saskia C de Jager, Adriaan O Kraaijeveld, Gerard Pasterkamp, Minke Smits, Jack A Schalken, Sylwia Łapińska-Szumczyk, Anna Łojkowska, Anna J Żaczek, Henk Lokhorst, Niels W C J van de Donk, Inger Nijhof, Henk-Jan Prins, Josée M Zijlstra, Sander Idema, Johannes C Baayen, Charlotte E Teunissen, Joep Killestein, Marc G Besselink, Lindsay Brammen, Thomas Bachleitner-Hofmann, Farrah Mateen, John T M Plukker, Michal Heger, Quirijn de Mast, Ton Lisman, D Michiel Pegtel, Harm-Jan Bogaard, Jacek Jassem, Anna Supernat, Niven Mehra, Winald Gerritsen, Cornelis D de Kroon, Christianne A R Lok, Jurgen M J Piek, Neeltje Steeghs, Winan J van Houdt, Ruud H Brakenhoff, Gabe S Sonke, Henk M Verheul, Elisa Giovannetti, Geert Kazemier, Siamack Sabrkhany, Ed Schuuring, Erik A Sistermans, Rob Wolthuis, Hanne Meijers-Heijboer, Josephine Dorsman, Cees Oudejans, Bauke Ylstra, Bart A Westerman, Daan van den Broek, Danijela Koppers-Lalic, Pieter Wesseling, R Jonas A Nilsson, W Peter Vandertop, David P Noske, Bakhos A Tannous, Nik Sol, Myron G Best, Thomas Wurdinger <<<

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening. <<<

Children with genetic diseases endure a prolonged and costly "diagnostic odyssey." The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved the diagnosis rate, ending the odyssey. However, the additional costs associated WES/WGS has impeded their adoption in Asian settings. We aim to estimate the expected change to the mean number of diagnostic tests used, and the associated costs from a decision to use WES early in the diagnostic pathways of pediatric phenotypes, as compared to Existing Practice. Retrospective data from a patient cohort recruited under the Singapore Undiagnosed Disease Program from a tertiary hospital in Singapore, for the period October 2004 to September 2020, was analyzed. Four phenotype-specific subgroups were used: multiple congenital anomalies (MCA) without developmental delay; global developmental delay (GDD); neuromuscular disorder (NMD) and primary immunodeficiency disorder (PID). Patients had undergone a traditional diagnostic pathway and received a diagnosis either through clinical exome or WES or WGS. A costs only analysis was performed, by tabulating the outcomes "test quantity" and "test costs" incurred by patients. The outcomes were compared with alternate diagnostic pathways which incorporates the early introduction of WES trio testing. To include uncertainty in cost outcomes, simulation studies were done on uncertain parameters. Cost outcomes are reported in Singapore dollars (S$). The 92 included patients had MCA (n = 48), GDD (n = 29), NMD (n = 10), or PID (n = 5). Patients were aged between 18 days and 26 years, 52.2% were males. The majority were of Chinese ethnicity (81.5%). If patients had access to WES directly, test quantity reduced by 97.38% for MCA, 96.98% for GDD, 96.56% for NMD, and 99.84% for PID. The expected cost savings per patient were $5940 for MCA (US$4433), $5342 for GDD (US$3986), $4622 for NMD (US$3449), and $58,497 for PID (US$43,654). Uncertainty assessment for MCA and GDD patients showed a respective likelihood of 86.9% and 97.4% for cost savings. Adoption of alternate diagnostic pathways with early WES in selected pediatric subgroups are likelt to reduce costs, when compared to Existing Practice. Benefits arising from earlier diagnosis, and the potential cost savings could mitigate the large initial cost of implementing WES in Asian settings. <<<

Recent breakthroughs in cancer immunotherapy and decreasing costs of high-throughput technologies have sparked intensive research into tumour-immune cell interactions using genomic tools. The wealth of the generated data and the added complexity pose considerable challenges and require computational tools to process, to analyse and to visualize the data. Recently, various tools have been developed and used to mine tumour immunologic and genomic data effectively and to provide novel mechanistic insights. Here, we review computational genomics tools for cancer immunology and provide information on the requirements and functionality in order to assist in the selection of tools and assembly of analytical pipelines. <<<

Zhi-Wei Guo , Ke Wang , Xiang Huang , Kun Li , Guojun Ouyang , Xu Yang , Jiayu Tan , Haihong Shi , Liangping Luo , Xincai Zhang , Min Zhang , Bo-Wei Han , Xiangming Zhai , Yingsong Wu , Fang Yang , Xue-Xi Yang , Jia Tang <<<

Preterm birth (PTB) occurs in around 11% of all births worldwide, resulting in significant morbidity and mortality for both mothers and offspring. Identification of pregnancies at risk of preterm birth in early pregnancy may help improve intervention and reduce its incidence. However, there exist few methods for PTB prediction developed with large sample size, high throughput screening and validation in independent cohorts. Here, we established a large scale, multi center, and case control study that included 2,590 pregnancies (2,072 full term and 518 preterm pregnancies) from three independent hospitals to develop a preterm birth classifier. We implemented whole genome sequencing on their plasma cfDNA and then their promoter profiling (read depth spanning from -1 KB to +1 KB around the transcriptional start site) was analyzed. Using three machine learning models and two feature selection algorithms, classifiers for predicting preterm delivery were developed. Among them, a classifier based on the support vector machine model and backward algorithm, named PTerm (Promoter profiling classifier for preterm prediction), exhibited the largest AUC value of 0.878 (0.852-0.904) following LOOCV cross validation. More importantly, PTerm exhibited good performance in three independent validation cohorts and achieved an overall AUC of 0.849 (0.831-0.866). Taken together, PTerm could be based on current noninvasive prenatal test (NIPT) data without changing its procedure or adding detection cost, which can be easily adapted for preclinical tests. <<<

Ja Hye Kim, Shinwon Hwang, Hyeonju Son, Dongsun Kim, Il Bin Kim, Myeong-Heui Kim, Nam Suk Sim, Dong Seok Kim, Yoo-Jin Ha, Junehawk Lee, Hoon-Chul Kang, Jeong Ho Lee, Sangwoo Kim <<<

Most somatic mutations that arise during normal development are present at low levels in single or multiple tissues depending on the developmental stage and affected organs. However, the effect of human developmental stages or mutations of different organs on the features of somatic mutations is still unclear. Here, we performed a systemic and comprehensive analysis of low-level somatic mutations using deep whole-exome sequencing (average read depth ~500×) of 498 multiple organ tissues with matched controls from 190 individuals. Our results showed that early clone-forming mutations shared between multiple organs were lower in number but showed higher allele frequencies than late clone-forming mutations [0.54 vs. 5.83 variants per individual; 6.17% vs. 1.5% variant allele frequency (VAF)] along with less nonsynonymous mutations and lower functional impacts. Additionally, early and late clone-forming mutations had unique mutational signatures that were distinct from mutations that originated from tumors. Compared with early clone-forming mutations that showed a clock-like signature across all organs or tissues studied, late clone-forming mutations showed organ, tissue, and cell-type specificity in the mutation counts, VAFs, and mutational signatures. In particular, analysis of brain somatic mutations showed a bimodal occurrence and temporal-lobe-specific signature. These findings provide new insights into the features of somatic mosaicism that are dependent on developmental stage and brain regions. <<<

Goutham Atla, Silvia Bonàs-Guarch, Mirabai Cuenca-Ardura, Anthony Beucher, Daniel J M Crouch, Javier Garcia-Hurtado, Ignasi Moran, T2DSystems Consortium, Manuel Irimia, Rashmi B Prasad, Anna L Gloyn, Lorella Marselli, Mara Suleiman, Thierry Berney, Eelco J P de Koning, Julie Kerr-Conte, Francois Pattou, John A Todd, Lorenzo Piemonti, Jorge Ferrer <<<

BACKGROUND: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.RESULTS: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.CONCLUSIONS: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit. <<<