In a search for the genetic basis for the structural difference between the related Streptococcus pneumoniae capsular serotypes 15B and 15C and for the reported reversible switching between these serotypes, the corresponding capsular polysaccharide synthesis (cps) loci were investigated by keeping in mind that at the structural level, the capsules differ only in O acetylation. The cps locus of a serotype 15B strain was identified, partially PCR amplified with primers based on the related serotype 14 sequence, and sequenced. Sequence analysis revealed, among other open reading frames, an intact open reading frame (designated cps15bM) whose product, at the protein level, exhibited characteristics of previously identified acetyltransferases. Genetic analysis of the corresponding region in a serotype15C strain indicated that the same gene was present but had a premature stop in translation. Closer analysis indicated that the serotype 15B gene contained a short tandem TA repeat consisting of eight TA units. In serotype 15C, this gene contained nine TA units that resulted in a frameshift and a truncated product. Genetic analysis of 17 serotype 15B and 15C clinical isolates revealed a perfect correlation between the serotype and the length of the short tandem repeat in the putative O-acetyltransferase gene. The number of TA repeating units varied between seven and nine in the various isolates. Together, the data strongly suggest that the structural difference between serotypes 15B and 15C is based on variation in the short tandem TA repeat in the O-acetyltransferase gene and that the transition between serotypes is due to slipped-strand mispairing with deletion or insertion of TA units in the cps15bM gene. <<<

Diffusion models are a class of deep generative models that have shown impressive results on various tasks with a solid theoretical foundation. Despite demonstrated success than state-of-the-art approaches, diffusion models often entail costly sampling procedures and sub-optimal likelihood estimation. Significant efforts have been made to improve the performance of diffusion models in various aspects. In this article, we present a comprehensive review of existing variants of diffusion models. Specifically, we provide the taxonomy of diffusion models and categorize them into three types: sampling-acceleration enhancement, likelihood-maximization enhancement, and data-generalization enhancement. We also introduce the other generative models (i.e., variational autoencoders, generative adversarial networks, normalizing flow, autoregressive models, and energy-based models) and discuss the connections between diffusion models and these generative models. Then we review the applications of diffusion models, including computer vision, natural language processing, waveform signal processing, multi-modal modeling, molecular graph generation, time series modeling, and adversarial purification. Furthermore, we propose new perspectives pertaining to the development of generative models. Github: this https URL. <<<

The ability to select short DNA oligonucleotide sequences capable of binding solely to their intended target is of great importance in developing nucleic acid based detection technologies. Applications such as multiplex PCR rely on primers binding to unique regions in a genome. Competing side reactions with other primer pairs or template DNA decrease PCR efficiency. Freely available primer design software such as Primer3 screens for potential hairpin and primer-dimer interactions while selecting a single primer pair. The development of multiplex PCR assays (in the range of 5 to 20 loci) requires the screening of all primer pairs for potential cross-reactivity. However, a logistical problem results due to the number of total number of comparisons required. Comparing the primer set for a 10-plex assay (20 total primer sequences) results in 210 primer-primer combinations that must be screened. The ability to screen sets of candidate oligomers rapidly for potential cross-reactivity reduces overall assay development time. Here we report the application of a familiar sliding algorithm for comparing two strands of DNA in an overlapping fashion. The algorithm has been employed in a software package wherein the user can compare multiple sequences in a single computational run. After the screening is completed, a score is assigned to potential duplex interactions exceeding a user-defined threshold. Additional criteria of predicted melting temperature (Tm) and free energy of melting (ΔG) are included for further ranking. Sodium counterion and total stand concentrations can be adjusted for the Tm and ΔG calculations. The predicted interactions are saved in a text file for further evaluation. <<<

Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained through sleep. Sleep consolidates recent memories and, concomitantly, could allow insight by changing their representational structure. Here we show a facilitating role of sleep in a process of insight. Subjects performed a cognitive task requiring the learning of stimulus-response sequences, in which they improved gradually by increasing response speed across task blocks. However, they could also improve abruptly after gaining insight into a hidden abstract rule underlying all sequences. Initial training establishing a task representation was followed by 8 h of nocturnal sleep, nocturnal wakefulness, or daytime wakefulness. At subsequent retesting, more than twice as many subjects gained insight into the hidden rule after sleep as after wakefulness, regardless of time of day. Sleep did not enhance insight in the absence of initial training. A characteristic antecedent of sleep-related insight was revealed in a slowing of reaction times across sleep. We conclude that sleep, by restructuring new memory representations, facilitates extraction of explicit knowledge and insightful behaviour. <<<

Dongqiang Zeng, Zilan Ye, Rongfang Shen, Guangchuang Yu, Jiani Wu, Yi Xiong, Rui Zhou, Wenjun Qiu, Na Huang, Li Sun, Xuejun Li, Jianping Bin, Yulin Liao, Min Shi, Wangjun Liao <<<

Recent advances in next-generation sequencing (NGS) technologies have triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to explore robust signatures for clinical translation is increasingly emphasized, and this is attributed to the clinical success of immune checkpoint blockades in diverse malignancies. However, effective tools for comprehensively interpreting multi-omics data are still warranted to provide increased granularity into the intrinsic mechanism of oncogenesis and immunotherapeutic sensitivity. Therefore, we developed a computational tool for effective Immuno-Oncology Biological Research (IOBR), providing a comprehensive investigation of the estimation of reported or user-built signatures, TME deconvolution, and signature construction based on multi-omics data. Notably, IOBR offers batch analyses of these signatures and their correlations with clinical phenotypes, long non-coding RNA (lncRNA) profiling, genomic characteristics, and signatures generated from single-cell RNA sequencing (scRNA-seq) data in different cancer settings. Additionally, IOBR integrates multiple existing microenvironmental deconvolution methodologies and signature construction tools for convenient comparison and selection. Collectively, IOBR is a user-friendly tool for leveraging multi-omics data to facilitate immuno-oncology exploration and to unveil tumor-immune interactions and accelerating precision immunotherapy. <<<

Yajie Zhao, Eugene J Gardner, Marcus A Tuke, Huairen Zhang, Maik Pietzner, Mine Koprulu, Raina Y Jia, Katherine S Ruth, Andrew R Wood, Robin N Beaumont, Jessica Tyrrell, Samuel E Jones, Hana Lango Allen, Felix R Day, Claudia Langenberg, Timothy M Frayling, Michael N Weedon, John R B Perry, Ken K Ong, Anna Murray <<<

PURPOSE: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes.METHODS: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data.RESULTS: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 × 10-8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10-6).CONCLUSION: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. <<<

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. <<<