Ever: Mitigating Hallucination in Large Language Models through Real-Time Verification and Rectification

Large Language Models (LLMs) have demonstrated remarkable proficiency in generating fluent text. However, they often encounter the challenge of generating inaccurate or hallucinated content. This issue is common in both non-retrieval-based generation and retrieval-augmented generation approaches, and existing post-hoc rectification methods may not address the accumulated hallucination errors that may be caused by the "snowballing" issue, especially in reasoning tasks. To tackle these challenges, we introduce a novel approach called Real-time Verification and Rectification (Ever). Instead of waiting until the end of the generation process to rectify hallucinations, Ever employs a real-time, step-wise generation and hallucination rectification strategy. The primary objective is to detect and rectify hallucinations as they occur during the text generation process. When compared to both retrieval-based and non-retrieval-based baselines, Ever demonstrates a significant improvement in generating trustworthy and factually accurate text across a diverse range of tasks, including short-form QA, biography generation, and multi-hop reasoning

Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway

Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts1. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes2. Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumors

Symbiosis of Arbuscular Mycorrhizal Fungi and <i>Lycium barbarum</i> L. Prefers NO₃⁻ over NH₄⁺

Nitrogen (N) is an essential nutrient that plants require and is, most of the time, limited in different terrestrial ecosystems. Forming symbioses with plants, arbuscular mycorrhizal (AM) fungi improve mineral element uptake and the net primary production of plants. Recent reports have suggested that AM fungi mediate N uptake in plants. However, there are fewer studies on the influence of AM fungi on the response of Lycium barbarum, a medicinal plant in northwest China, under different N-addition conditions. In this study, the effect of Rhizophagus irregularis, N forms (NO3− and NH4+), and N levels (1.5, 7.5, 15, 30 mM) on the performance of L. barbarum was evaluated through a pot experiment. The application of R. irregularis significantly improved L. barbarum biomass, net photosynthetic rate, and root tissue viability under adequate NO3− and NH4+ supplies, and mycorrhizal plants showed better performance under NO3− supply. AM colonization enhanced N acquisition under adequate NO3− supply and strongly induced the expression of LbAMT3-1 in L. barbarum roots. Based on these results, we propose that NO3−-dominated N supply favors mycorrhizal symbiosis to a greater extent than NH4+; this study provides a basis for maintaining beneficial AM symbiosis during nitrogen fertilizer use in arable land

Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer

The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to α-ketoglutarate (α-KG) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease