A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma.

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

Bi-Directional Ensemble Feature Reconstruction Network for Few-Shot Fine-Grained Classification.

The main challenge for fine-grained few-shot image classification is to learn feature representations with higher inter-class and lower intra-class variations, with a mere few labelled samples. Conventional few-shot learning methods however cannot be naively adopted for this fine-grained setting - a quick pilot study reveals that they in fact push for the opposite (i.e., lower inter-class variations and higher intra-class variations). To alleviate this problem, prior works predominately use a support set to reconstruct the query image and then utilize metric learning to determine its category. Upon careful inspection, we further reveal that such unidirectional reconstruction methods only help to increase inter-class variations and are not effective in tackling intra-class variations. In this paper, we introduce a bi-reconstruction mechanism that can simultaneously accommodate for inter-class and intra-class variations. In addition to using the support set to reconstruct the query set for increasing inter-class variations, we further use the query set to reconstruct the support set for reducing intra-class variations. This design effectively helps the model to explore more subtle and discriminative features which is key for the fine-grained problem in hand. Furthermore, we also construct a self-reconstruction module to work alongside the bi-directional module to make the features even more discriminative. We introduce the snapshot ensemble method in the episodic learning strategy - a simple trick to further improve model performance without increasing training costs. Experimental results on three widely used fine-grained image classification datasets, as well as general and cross-domain few-shot image datasets, consistently show considerable improvements compared with other methods. Codes are available at https://github.com/PRIS-CV/BiEN.

CreativeSeg: Semantic Segmentation of Creative Sketches.

The problem of sketch semantic segmentation is far from being solved. Despite existing methods exhibiting near-saturating performances on simple sketches with high recognisability, they suffer serious setbacks when the target sketches are products of an imaginative process with high degree of creativity. We hypothesise that human creativity, being highly individualistic, induces a significant shift in distribution of sketches, leading to poor model generalisation. Such hypothesis, backed by empirical evidences, opens the door for a solution that explicitly disentangles creativity while learning sketch representations. We materialise this by crafting a learnable creativity estimator that assigns a scalar score of creativity to each sketch. It follows that we introduce CreativeSeg, a learning-to-learn framework that leverages the estimator in order to learn creativity-agnostic representation, and eventually the downstream semantic segmentation task. We empirically verify the superiority of CreativeSeg on the recent "Creative Birds" and "Creative Creatures" creative sketch datasets. Through a human study, we further strengthen the case that the learned creativity score does indeed have a positive correlation with the subjective creativity of human. Codes are available at https://github.com/PRIS-CV/Sketch-CS.

Semi-Supervised Learning for FGVC With Out-of-Category Data.

Despite great strides made on fine-grained visual classification (FGVC), current methods are still heavily reliant on fully-supervised paradigms where ample expert labels are called for. Semi-supervised learning (SSL) techniques, acquiring knowledge from unlabeled data, provide a considerable means forward and have shown great promise for coarse-grained problems. However, exiting SSL paradigms mostly assume in-category (i.e., category-aligned) unlabeled data, which hinders their effectiveness when re-proposed on FGVC. In this paper, we put forward a novel design specifically aimed at making out-of-category data work for semi-supervised FGVC. We work off an important assumption that all fine-grained categories naturally follow a hierarchical structure (e.g., the phylogenetic tree of "Aves" that covers all bird species). It follows that, instead of operating on individual samples, we can instead predict sample relations within this tree structure as the optimization goal of SSL. Beyond this, we further introduced two strategies uniquely brought by these tree structures to achieve inter-sample consistency regularization and reliable pseudo-relation. Our experimental results reveal that (i) the proposed method yields good robustness against out-of-category data, and (ii) it can be equipped with prior arts, boosting their performance thus yielding state-of-the-art results.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Pan-cancer proteogenomics connects oncogenic drivers to functional states.

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.

Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin.

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.

Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation.

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.

Sketch-Segformer: Transformer-Based Segmentation for Figurative and Creative Sketches.

Sketch is a well-researched topic in the vision community by now. Sketch semantic segmentation in particular, serves as a fundamental step towards finer-level sketch interpretation. Recent works use various means of extracting discriminative features from sketches and have achieved considerable improvements on segmentation accuracy. Common approaches for this include attending to the sketch-image as a whole, its stroke-level representation or the sequence information embedded in it. However, they mostly focus on only a part of such multi-facet information. In this paper, we for the first time demonstrate that there is complementary information to be explored across all these three facets of sketch data, and that segmentation performance consequently benefits as a result of such exploration of sketch-specific information. Specifically, we propose the Sketch-Segformer, a transformer-based framework for sketch semantic segmentation that inherently treats sketches as stroke sequences other than pixel-maps. In particular, Sketch-Segformer introduces two types of self-attention modules having similar structures that work with different receptive fields (i.e., whole sketch or individual stroke). The order embedding is then further synergized with spatial embeddings learned from the entire sketch as well as localized stroke-level information. Extensive experiments show that our sketch-specific design is not only able to obtain state-of-the-art performance on traditional figurative sketches (such as SPG, SketchSeg-150K datasets), but also performs well on creative sketches that do not conform to conventional object semantics (CreativeSketch dataset) thanks for our usage of multi-facet sketch information. Ablation studies, visualizations, and invariance tests further justifies our design choice and the effectiveness of Sketch-Segformer. Codes are available at https://github.com/PRIS-CV/Sketch-SF.

A flexible quasi-likelihood model for microbiome abundance count data.

In this article, we present a flexible model for microbiome count data. We consider a quasi-likelihood framework, in which we do not make any assumptions on the distribution of the microbiome count except that its variance is an unknown but smooth function of the mean. By comparing our model to the negative binomial generalized linear model (GLM) and Poisson GLM in simulation studies, we show that our flexible quasi-likelihood method yields valid inferential results. Using a real microbiome study, we demonstrate the utility of our method by examining the relationship between adenomas and microbiota. We also provide an R package "fql" for the application of our method.

Clinical evidence for a role of E2F1-induced replication stress in modulating tumor mutational burden and immune microenvironment.

DNA replication stress (RS) is frequently induced by oncogene activation and is believed to promote tumorigenesis. However, clinical evidence for the role of oncogene-induced RS in tumorigenesis remains scarce, and the mechanisms by which RS promotes cancer development remain incompletely understood. By performing a series of bioinformatic analyses on the oncogene E2F1, other RS-inducing factors, and replication fork processing factors in TCGA cancer database using previously established tools, we show that hyperactivity of E2F1 likely promotes the expression of several of these factors in virtually all types of cancer to induce RS and cytosolic self-DNA production. In addition, the expression of these factors positively correlates with that of ATR and Chk1 that govern the cellular response to RS, the tumor mutational load, and tumor infiltration of immune-suppressive CD4+Th2 cells and myeloid-derived suppressor cells (MDSCs). Consistently, high expression of these factors is associated with poor patient survival. Our study provides new insights into the role of E2F1-induced RS in tumorigenesis and suggests therapeutic approaches for E2F1-overexpressing cancers by targeting genomic instability, cytosolic self-DNA and the tumor immune microenvironment.

Uncertainty-Aware Source-Free Domain Adaptive Semantic Segmentation.

Source-Free Domain Adaptation (SFDA) is becoming topical to address the challenge of distribution shift between training and deployment data, while also relaxing the requirement of source data availability during target domain adaptation. In this paper, we focus on SFDA for semantic segmentation, in which pseudo labeling based target domain self-training is a common solution. However, pseudo labels generated by the source models are particularly unreliable on the target domain data due to the domain shift issue. Therefore, we propose to use Bayesian Neural Network (BNN) to improve the target self-training by better estimating and exploiting pseudo-label uncertainty. With the uncertainty estimation of BNNs, we introduce two novel self-training based components: Uncertainty-aware Online Teacher-Student Learning (UOTSL) and Uncertainty-aware FeatureMix (UFM). Extensive experiments on two popular benchmarks, GTA 5 → Cityscapes and SYNTHIA → Cityscapes, show the superiority of our proposed method with mIoU gains of 3.6% and 5.7% over the state-of-the-art respectively.

Prediction Calibration for Generalized Few-Shot Semantic Segmentation.

Generalized Few-shot Semantic Segmentation (GFSS) aims to segment each image pixel into either base classes with abundant training examples or novel classes with only a handful of (e. g., 1-5) training images per class. Compared to the widely studied Few-shot Semantic Segmentation (FSS), which is limited to segmenting novel classes only, GFSS is much under-studied despite being more practical. Existing approach to GFSS is based on classifier parameter fusion whereby a newly trained novel class classifier and a pre-trained base class classifier are combined to form a new classifier. As the training data is dominated by base classes, this approach is inevitably biased towards the base classes. In this work, we propose a novel Prediction Calibration Network (PCN) to address this problem. Instead of fusing the classifier parameters, we fuse the scores produced separately by the base and novel classifiers. To ensure that the fused scores are not biased to either the base or novel classes, a new Transformer-based calibration module is introduced. It is known that the lower-level features are useful of detecting edge information in an input image than higher-level features. Thus, we build a cross-attention module that guides the classifier's final prediction using the fused multi-level features. However, transformers are computationally demanding. Crucially, to make the proposed cross-attention module training tractable at the pixel level, this module is designed based on feature-score cross-covariance and episodically trained to be generalizable at inference time. Extensive experiments on PASCAL- 5i and COCO- 20i show that our PCN outperforms the state-the-the-art alternatives by large margins.

Making a Bird AI Expert Work for You and Me.

As powerful as fine-grained visual classification (FGVC) is, responding your query with a bird name of "Whip-poor-will" or "Mallard" probably does not make much sense. This however commonly accepted in the literature, underlines a fundamental question interfacing AI and human - what constitutes transferable knowledge for human to learn from AI? This paper sets out to answer this very question using FGVC as a test bed. Specifically, we envisage a scenario where a trained FGVC model (the AI expert) functions as a knowledge provider in enabling average people (you and me) to become better domain experts ourselves. Assuming an AI expert trained using expert human labels, we anchor our focus on asking and providing solutions for two questions: (i) what is the best transferable knowledge we can extract from AI, and (ii) what is the most practical means to measure the gains in expertise given that knowledge? We propose to represent knowledge as highly discriminative visual regions that are expert-exclusive and instantiate it via a novel multi-stage learning framework. A human study of 15,000 trials shows our method is able to consistently improve people of divergent bird expertise to recognise once unrecognisable birds. We further propose a crude but benchmarkable metric TEMI and therefore allow future efforts in this direction to be comparable to ours without the need of large-scale human studies.

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries.

OBJECTIVE: To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. METHODS: We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. RESULTS: The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. DISCUSSION/CONCLUSION: Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma.

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. SIGNIFICANCE: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy.

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

Deep Learning for Free-Hand Sketch: A Survey.

Free-hand sketches are highly illustrative, and have been widely used by humans to depict objects or stories from ancient times to the present. The recent prevalence of touchscreen devices has made sketch creation a much easier task than ever and consequently made sketch-oriented applications increasingly popular. The progress of deep learning has immensely benefited free-hand sketch research and applications. This paper presents a comprehensive survey of the deep learning techniques oriented at free-hand sketch data, and the applications that they enable. The main contents of this survey include: (i) A discussion of the intrinsic traits and unique challenges of free-hand sketch, to highlight the essential differences between sketch data and other data modalities, e.g., natural photos. (ii) A review of the developments of free-hand sketch research in the deep learning era, by surveying existing datasets, research topics, and the state-of-the-art methods through a detailed taxonomy and experimental evaluation. (iii) Promotion of future work via a discussion of bottlenecks, open problems, and potential research directions for the community.

Dynamic Instance Domain Adaptation.

Most existing studies on unsupervised domain adaptation (UDA) assume that each domain's training samples come with domain labels (e.g., painting, photo). Samples from each domain are assumed to follow the same distribution and the domain labels are exploited to learn domain-invariant features via feature alignment. However, such an assumption often does not hold true-there often exist numerous finer-grained domains (e.g., dozens of modern painting styles have been developed, each differing dramatically from those of the classic styles). Therefore, forcing feature distribution alignment across each artificially-defined and coarse-grained domain can be ineffective. In this paper, we address both single-source and multi-source UDA from a completely different perspective, which is to view each instance as a fine domain. Feature alignment across domains is thus redundant. Instead, we propose to perform dynamic instance domain adaptation (DIDA). Concretely, a dynamic neural network with adaptive convolutional kernels is developed to generate instance-adaptive residuals to adapt domain-agnostic deep features to each individual instance. This enables a shared classifier to be applied to both source and target domain data without relying on any domain annotation. Further, instead of imposing intricate feature alignment losses, we adopt a simple semi-supervised learning paradigm using only a cross-entropy loss for both labeled source and pseudo labeled target data. Our model, dubbed DIDA-Net, achieves state-of-the-art performance on several commonly used single-source and multi-source UDA datasets including Digits, Office-Home, DomainNet, Digit-Five, and PACS.

One Sketch for All: One-Shot Personalized Sketch Segmentation.

We present the first one-shot personalized sketch segmentation method. We aim to segment all sketches belonging to the same category provisioned with a single sketch with a given part annotation while (i) preserving the parts semantics embedded in the exemplar, and (ii) being robust to input style and abstraction. We refer to this scenario as personalized. With that, we importantly enable a much-desired personalization capability for downstream fine-grained sketch analysis tasks. To train a robust segmentation module, we deform the exemplar sketch to each of the available sketches of the same category. Our method generalizes to sketches not observed during training. Our central contribution is a sketch-specific hierarchical deformation network. Given a multi-level sketch-strokes encoding obtained via a graph convolutional network, our method estimates rigid-body transformation from the target to the exemplar, on the upper level. Finer deformation from the exemplar to the globally warped target sketch is further obtained through stroke-wise deformations, on the lower-level. Both levels of deformation are guided by mean squared distances between the keypoints learned without supervision, ensuring that the stroke semantics are preserved. We evaluate our method against the state-of-the-art segmentation and perceptual grouping baselines re-purposed for the one-shot setting and against two few-shot 3D shape segmentation methods. We show that our method outperforms all the alternatives by more than 10% on average. Ablation studies further demonstrate that our method is robust to personalization: changes in input part semantics and style differences.