Improving Contrastive Learning of Sentence Embeddings with Focal-InfoNCE

The recent success of SimCSE has greatly advanced state-of-the-art sentence representations. However, the original formulation of SimCSE does not fully exploit the potential of hard negative samples in contrastive learning. This study introduces an unsupervised contrastive learning framework that combines SimCSE with hard negative mining, aiming to enhance the quality of sentence embeddings. The proposed focal-InfoNCE function introduces self-paced modulation terms in the contrastive objective, downweighting the loss associated with easy negatives and encouraging the model focusing on hard negatives. Experimentation on various STS benchmarks shows that our method improves sentence embeddings in terms of Spearman's correlation and representation alignment and uniformity.Comment: Findings of emnlp 202

Artificial Intelligence Framework Identifies Candidate Targets for Drug Repurposing in Alzheimer’s Disease

Background: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein–protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein–protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results: Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861–0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862–0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions: In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD

Multimodal Single-Cell/Nucleus RNA Sequencing Data Analysis Uncovers Molecular Networks Between Disease-Associated Microglia and Astrocytes With Implications for Drug Repurposing in Alzheimer’s Disease

Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer\u27s disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metaboliteenzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P \u3c 1.0 × 10 - 8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P \u3c 1.0 × 10 - 8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD

Improving Adversarial Robustness with Self-Paced Hard-Class Pair Reweighting

Deep Neural Networks are vulnerable to adversarial attacks. Among many defense strategies, adversarial training with untargeted attacks is one of the most effective methods. Theoretically, adversarial perturbation in untargeted attacks can be added along arbitrary directions and the predicted labels of untargeted attacks should be unpredictable. However, we find that the naturally imbalanced inter-class semantic similarity makes those hard-class pairs become virtual targets of each other. This study investigates the impact of such closely-coupled classes on adversarial attacks and develops a self-paced reweighting strategy in adversarial training accordingly. Specifically, we propose to upweight hard-class pair losses in model optimization, which prompts learning discriminative features from hard classes. We further incorporate a term to quantify hard-class pair consistency in adversarial training, which greatly boosts model robustness. Extensive experiments show that the proposed adversarial training method achieves superior robustness performance over state-of-the-art defenses against a wide range of adversarial attacks. The code of the proposed SPAT is published at https://github.com/puerrrr/Self-Paced-Adversarial-Training

Effect of Kaolin/TiO₂ Additions and Contact Temperature on the Interaction between DD6 Alloys and Al₂O₃ Shells

In this study, the effects of kaolin and TiO2 additions on the interaction between DD6 alloys and Al2O3 shells were investigated at 1550 and 1600 °C, respectively. Through the use of optical microscopy and scanning electron microscopy, the phase composition and microstructure of the shells and the alloys were studied, and the interaction mechanism was clarified. The results indicate that the shells adding kaolin and TiO2 had a relatively weak interaction with the alloys at 1550 °C, and no significant sand adhesion could be observed. As the contact temperature was increased to 1600 °C, the alloy melt could permeate into the shells, resulting in the generation of a thick sand adhesion layer. The thicknesses of the attached layers in the alloys, which contacted the shell with kaolin and TiO2, were 120 and 220 μm, respectively. No significant chemical products could be detected in the interaction layer, meaning that only physical dissolution of the shell refractory occurred. This study provides an experimental foundation for improving shell performance and offers valuable references for further research in related fields

Reducing acetylated tau is neuroprotective in brain injury

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer’s disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.[Display omitted]•Brain injury induces Alzheimer’s disease-like neuronal ac-tau•Neurodegenerative brain injury is reflected by ac-tau blood levels in mice and people•Decreasing ac-tau after brain injury at multiple signaling nodes is neuroprotective•Ac-tau-inhibiting medicines are associated with reduced neurodegenerative diseaseReducing brain injury-induced neuronal tau acetylation is neuroprotective in traumatic brain injury and has a role in Alzheimer’s disease pathogenesis