Artem Sokolov

Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer’s disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72 -ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer’s disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals TYK2 as a top hit, and TYK2 knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer’s disease and C9ORF72 -ALS.

Spatial proteomics (highly multiplexed tissue imaging) provides unprecedented insight into the types, states, and spatial organization of cells within preserved tissue environments. To enable single-cell analysis, high-plex images are typically segmented using algorithms that assign marker signals to individual cells. However, conventional segmentation is often imprecise and susceptible to signal spillover between adjacent cells, interfering with accurate cell type identification. Segmentation-based methods also fail to capture the morphological detail that histopathologists rely on for disease diagnosis and staging. Here, we present a method that combines unsupervised, pixel-level machine learning using autoencoders with traditional segmentation to generate single-cell data that captures information on protein abundance, morphology, and local neighborhood in a manner analogous to human experts while overcoming signal spillover. We demonstrate the generality of this approach by applying it to CyCIF, Lunaphore COMET, and CODEX data, and show that it can learn histological features across multiple spatial scales.

The National Cancer Institute (NCI) supports numerous research consortia that rely on imaging technologies to study cancerous tissues. To foster collaboration and innovation in this field, the Image Analysis Working Group (IAWG) was created in 2019. As multiplexed imaging techniques grow in scale and complexity, more advanced computational methods are required beyond traditional approaches like segmentation and pixel intensity quantification. In 2022, the IAWG held a virtual hackathon focused on addressing challenges in analyzing complex, high‐dimensional datasets from fixed cancer tissues. The hackathon addressed key challenges in three areas: (1) cell type classification and assessment, (2) spatial data visualization and translation, and (3) scaling image analysis for large, multi‐terabyte datasets. Participants explored the limitations of current automated analysis tools, developed potential solutions, and made significant progress during the hackathon. Here we provide a summary of the efforts and resultant resources and highlight remaining challenges facing the research community as emerging technologies are integrated into diverse imaging modalities and data analysis platforms.

Increasingly larger datasets have become a standard ingredient to advancing the state-of-the-art in NLP. However, data quality might have already become the bottleneck to unlock further gains. Given the diversity and the sizes of modern datasets, standard data filtering is not straight-forward to apply, because of the multifacetedness of the harmful data and elusiveness of filtering rules that would generalize across multiple tasks. We study the fitness of task-agnostic self-influence scores of training examples for data cleaning, analyze their efficacy in capturing naturally occurring outliers, and investigate to what extent self-influence based data cleaning can improve downstream performance in machine translation, question answering and text classification, building up on recent approaches to self-influence calculation and automated curriculum learning.

The National Cancer Institute (NCI) supports many research programs and consortia, many of which use imaging as a major modality for characterizing cancerous tissue. A trans-consortia Image Analysis Working Group (IAWG) was established in 2019 with a mission to disseminate imaging-related work and foster collaborations. In 2022, the IAWG held a virtual hackathon focused on addressing challenges of analyzing high dimensional datasets from fixed cancerous tissues. Standard image processing techniques have automated feature extraction, but the next generation of imaging data requires more advanced methods to fully utilize the available information. In this perspective, we discuss current limitations of the automated analysis of multiplexed tissue images, the first steps toward deeper understanding of these limitations, what possible solutions have been developed, any new or refined approaches that were developed during the Image Analysis Hackathon 2022, and where further effort is required. The outstanding problems addressed in the hackathon fell into three main themes: 1) challenges to cell type classification and assessment, 2) translation and visual representation of spatial aspects of high dimensional data, and 3) scaling digital image analyses to large (multi-TB) datasets. We describe the rationale for each specific challenge and the progress made toward addressing it during the hackathon. We also suggest areas that would benefit from more focus and offer insight into broader challenges that the community will need to address as new technologies are developed and integrated into the broad range of image-based modalities and analytical resources already in use within the cancer research community.

End-to-end automatic speech translation (AST) relies on data that combines audio inputs with text translation outputs. Previous work used existing large parallel corpora of transcriptions and translations in a knowledge distillation (KD) setup to distill a neural machine translation (NMT) into an AST student model. While KD allows using larger pretrained models, the reliance of previous KD approaches on manual audio transcripts in the data pipeline restricts the applicability of this framework to AST. We present an imitation learning approach where a teacher NMT system corrects the errors of an AST student without relying on manual transcripts. We show that the NMT teacher can recover from errors in automatic transcriptions and is able to correct erroneous translations of the AST student, leading to improvements of about 4 BLEU points over the standard AST end-to-end baseline on the English-German CoVoST-2 and MuST-C datasets, respectively. Code and data are publicly available.\footnote{\url{https://github.com/HubReb/imitkd_ast/releases/tag/v1.1}}

Irina Bejan, Artem Sokolov, Katja Filippova. Proceedings of the 2023 Conference on Empirical Methods in Natural Language Processing. 2023.

Rebekka Hubert, Artem Sokolov, Stefan Riezler. Proceedings of the 20th International Conference on Spoken Language Translation (IWSLT 2023). 2023.

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin’s action in the brain.