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Large language models (LLMs) have made a significant impact on the fields of general artificial intelligence. General purpose LLMs exhibit strong logic and reasoning skills and general world knowledge but can sometimes generate misleading results when prompted on specific subject areas. LLMs trained with domain-specific knowledge can reduce the generation of misleading information (i.e. hallucinations) and enhance the precision of LLMs in specialized contexts. Training new LLMs on specific corpora however can be resource intensive. Here we explored the use of a retrieval-augmented generation (RAG) model which we tested on literature specific to a biomedical research area. OpenAI’s GPT-3.5, GPT-4, Microsoft’s Prometheus, and a custom RAG model were used to answer 19 questions pertaining to diffuse large B-cell lymphoma (DLBCL) disease biology and treatment. Eight independent reviewers assessed LLM responses based on accuracy, relevance, and readability, rating responses on a 3-point scale for each category. These scores were then used to compare LLM performance. The performance of the LLMs varied across scoring categories. On accuracy and relevance, the RAG model outperformed other models with higher scores on average and the most top scores across questions. GPT-4 was more comparable to the RAG model on relevance versus accuracy. By the same measures, GPT-4 and GPT-3.5 had the highest scores for readability of answers when compared to the other LLMs. GPT-4 and 3.5 also had more answers with hallucinations than the other LLMs, due to non-existent references and inaccurate responses to clinical questions. Our findings suggest that an oncology research-focused RAG model may outperform general-purpose LLMs in accuracy and relevance when answering subject-related questions. This framework can be tailored to Q&A in other subject areas. Further research will help understand the impact of LLM architectures, RAG methodologies, and prompting techniques in answering questions across different subject areas.

Growing evidence suggests that peripheral factors to the brain driving neuro-inflammation could affect Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) severity. Herpes simplex virus type 1 (HSV1) infection has been associated with AD while other related viruses, including cytomegalovirus (CMV), Epstein-Bar virus and human herpesvirus 6 (HHV6), are known to infect neurons. Here we compare gene expression profiles between AD or PD patients to those afflicted with herpes viral infections as to discover novel potential neuro-inflammation pathways. We found multiple significant differentially expressed genes (DEGs) shared between AD/PD and viral infections including SESN3 which has a genetic association for increased AD risk. Pathway enrichment analysis revealed viruses shared Oxidative Stress Defense System and LRRK2 pathways with AD and PD, respectively. We further processed our data to identify novel target and drug-repurposing opportunities including anti-inflammatory therapy, immune-modulators and cholinesterase inhibitors which could lead to new therapeutics paradigms for these neurodegenerative diseases.

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2 + neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2 + neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention. Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.

IntroductionInterleukin (IL) 22 is a key cytokine involved in regulation of epithelial function and its role in IBD remains highly controversial. Some studies indicate a protective role in epithelial regeneration, whereas other studies imply a pro-inflammatory role. Insights are now needed to improve of understanding of the functional role of this important cytokine and how its expression might impact patients with ulcerative colitis (UC). In this study, we have probed the clinical and functional significance of IL-22 responsive transcriptional modules and causal networks in diseased tissue of over 500 UC patients and in preclinical models of colitis.MethodsWe mapped the transcriptional landscape of human colonic epithelial 3D mini-gut organoids in response to treatment with IL22, and other pro-inflammatory cytokines. We tested the clinical significance of the IL22-regulated transcriptome by probing whole colonic biopsies from 550 ulcerative colitis (UC) patients from UNIFI clinical trial programme (patients with UC treated with ustekinumab, an anti-IL12p40 antibody). The functional role of IL22 regulated biological pathways were evaluated in pre-clinical models of UC.ResultsIL-22 regulated pro-inflammatory biological pathways involved in microbial recognition, cancer and immune cell chemotaxis. IL-22 was an especially potent regulator of the CXC family chemokines CXCL1, CXCL2, CXCL5, CXCL6 and CXCL8, which are all powerful neutrophil-selective chemokines. There was a positive correlation between the IL-22 transcriptional programme and the histological severity of inflammation (r=0.49, p<0.0001) and, in particular, neutrophil infiltration in lamina propria and the colonic epithelium of patients with UC. Patients with the greatest magnitude of enrichment for IL22-responisve transcripts in whole colonic biopsies sampled immediately prior to ustekinumab initiation was associated with failure to achieve mucosal healing (8%) in comparison with patients with low enrichment scores (25%, P=0.002) at week 8 following induction.IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression was highly conserved across species and was dependent on JAK1/STAT3 signalling. In preclinical models of colitis, IL-22 induction of neutrophil-active chemokines was functionally and pathologically important in the recruitment of CXCR2+ neutrophils to the colon.ConclusionsThe interleukin 22/neutrophil axis is functionally important in colitis and is associated with treatment resistance in ulcerative colitis

Large language models (LLMs) have made significant advancements in natural language processing (NLP). Broad corpora capture diverse patterns but can introduce irrelevance, while focused corpora enhance reliability by reducing misleading information. Training LLMs on focused corpora poses computational challenges. An alternative approach is to use a retrieval-augmentation (RetA) method tested in a specific domain. To evaluate LLM performance, OpenAI's GPT-3, GPT-4, Bing's Prometheus, and a custom RetA model were compared using 19 questions on diffuse large B-cell lymphoma (DLBCL) disease. Eight independent reviewers assessed responses based on accuracy, relevance, and readability (rated 1-3). The RetA model performed best in accuracy (12/19 3-point scores, total=47) and relevance (13/19, 50), followed by GPT-4 (8/19, 43; 11/19, 49). GPT-4 received the highest readability scores (17/19, 55), followed by GPT-3 (15/19, 53) and the RetA model (11/19, 47). Prometheus underperformed in accuracy (34), relevance (32), and readability (38). Both GPT-3.5 and GPT-4 had more hallucinations in all 19 responses compared to the RetA model and Prometheus. Hallucinations were mostly associated with non-existent references or fabricated efficacy data. These findings suggest that RetA models, supplemented with domain-specific corpora, may outperform general-purpose LLMs in accuracy and relevance within specific domains. However, this evaluation was limited to specific questions and metrics and may not capture challenges in semantic search and other NLP tasks. Further research will explore different LLM architectures, RetA methodologies, and evaluation methods to assess strengths and limitations more comprehensively.

TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 μL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-β and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk and WT AMs, confirming its importance during inflammation. This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

Infectious and Parasitic Diseases (IPD) remain a challenge for medicine due to several interconnected reasons, such as antimicrobial resistance (AMR). American tegumentary leishmaniasis (ATL) is an overlooked IPD causing persistent skin ulcers that are challenging to heal, resulting in disfiguring scars. Moreover, it has the potential to extend from the skin to the mucous membranes of the nose, mouth, and throat in both humans and various animals. Given the limited effectiveness and AMR of current drugs, the exploration of new substances has emerged as a promising alternative for ATL treatment. Arrabidaea brachypoda (DC). Bureau is a native Brazilian plant rich in dimeric flavonoids, including Brachydin (BRA), which displays antimicrobial activity, but still little has been explored regarding the development of therapeutic formulations. In this work, we present the design of a low-cost liquid formulation based on the use of Pluronic F127 for encapsulation of high BRA concentration (LF-B500). The characterization techniques revealed that BRA-loaded F127 micelles are well-stabilized in an unusual worm-like form. The in vitro cytotoxicity assay demonstrated that LF-B500 was non-toxic to macrophages but efficient in the inactivation of forms of Leishmania amazonensis promastigotes with IC50 of 16.06 µg/mL. The results demonstrated that LF-B500 opened a new perspective on the use of liquid formulation-based natural products for ATL treatment.

The monitoring and combined use of dietary supplements to restore adequate growth are paramount and highly recommended in child malnutrition, an important public health problem. The objective of this study was to analyze the effects of cashew nut seed flour in children with moderate malnutrition, treated at primary healthcare services. This is a randomized clinical trial conducted from April to October 2017 in the city of Imperatriz, Brazil. The sample comprised 30 children born at term, aged between 2 and 5 years, and newly diagnosed with malnutrition (60 days or less), randomized into experimental and control groups. The intervention consisted of daily intake of cashew nut seed flour. There was intragroup statistically significant difference in the glucose levels of children who were assigned to the control group (p=0.02) and in the glycated hemoglobin in the experimental group (p<0.01). Intergroup analysis of glycated hemoglobin levels showed statistically significant differences in favor of the experimental group (p=0.01). HDL and LDL had, respectively, increased and decreased in the experimental group. The use of cashew nut seed flour in a 24-week period had positive effects on glycated hemoglobin, HDL, and LDL parameters in moderately malnourished children.

The monitoring and combined use of dietary supplements to restore adequate growth are paramount and highly recommended in child malnutrition, an important public health problem. The objective of this study was to analyze the effects of cashew nut seed flour in children with moderate malnutrition, treated at primary healthcare services. This is a randomized clinical trial conducted from April to October 2017 in the city of Imperatriz, Brazil. The sample comprised 30 children born at term, aged between 2 and 5 years, and newly diagnosed with malnutrition (60 days or less), randomized into experimental and control groups. The intervention consisted of daily intake of cashew nut seed flour. There was intragroup statistically significant difference in the glucose levels of children who were assigned to the control group (p = 0.02) and in the glycated hemoglobin in the experimental group (p < 0.01). Intergroup analysis of glycated hemoglobin levels showed statistically significant differences in favor of the experimental group (p = 0.01). HDL and LDL had, respectively, increased and decreased in the experimental group. The use of cashew nut seed flour in a 24-week period had positive effects on glycated hemoglobin, HDL, and LDL parameters in moderately malnourished children.