CACHING OF RETRIEVAL AUGMENTED GENERATION MODEL TRAINED WITH DYNAMIC DATA AND DYNAMICALLY UPDATING OF CACHE

Techniques are presented herein provide for an intelligent caching mechanism of a Retrieval Augmented Generation (RAG) model trained with dynamic data which is subject to get deleted or modified periodically. Based on the feedback from the customer, Cache Vector DB is updated. This method is capable of processing positive and negative feedback from customers to update the Cache Vector DB while simultaneously protecting from negative feedback spam. The method leverages a framework that not only caches an original question/query (primary) and the corresponding response, but also secondary question/queries which either uses GenAI to create synthetic queries of the original question/query or the queries which get positive feedback of an answer fetched from the caching. Also, keeping the cache updated once the source document is modified is a key point of this process. This strategy increases the likelihood of hitting the Cache Vector DB decreasing the amount of processing time and reduces the cost to deliver an answer

Targeted Mutation Detection in Advanced Breast Cancer Using MammaSeq Identifies RET as a Potential Contributor to Breast Cancer Metastasis

The lack of any reported breast cancer specific diagnostic NGS tests inspired the development of MammaSeq, an amplicon based NGS panel built specifically for use in advanced breast cancer. In a pilot study to define the clinical utility of the panel, 46 solid tumor samples, plus an additional 14 samples of circulating-free DNA (cfDNA) from patients with advanced breast cancer were sequenced and analyzed using the OncoKB precision oncology database. We identified 26 clinically actionable variants (levels 1-3) annotated by the OncoKB precision oncology database, distributed across 20 out of 46 solid tumor cases (40%), and 4 clinically actionable mutations distributed across 4 samples in the 14 cfDNA sample cohort (29%). The mutation allele (MAF) frequencies of ESR1-D538G and FOXA1-Y175C mutations correlated with CA.27.29 levels in patient-matched blood, indicating that MAF may be a reliable marker for disease burden. Interestingly, 4 of the mutations found in metastatic samples occurred in the gene RET, an oncogenic receptor tyrosine kinase. In an orthogonal study, the lab has recently identified RET as one of the most recurrently upregulated genes in breast cancer brain metastases. Interestingly, the ligand for RET is the family of glial-cell derived neurotrophic factors (GDNF), a growth factor secreted by glial cells of the central nervous system. This lead to the hypothesis that RET overexpression facilitates breast cancer brain metastasis in response to the high levels of GDNF, while RET activating point mutations increase metastatic capacity without specific organ tropism. While the effect of GDNF treatment on proliferation in 2D was limited, in ultra-low attachment (ULA) plates we saw a significant increase in anchorage independent growth of MCF-7 cells. To determine if GDNF acts as a chemoattractant for RET positive BrCa cells, we utilized a transwell migration assay, with GDNF as the sole chemoattractant. When RET was overexpressed, there was a visual increase in cell migration. Together, these studies demonstrate the clinical feasibility of using MammaSeq to detect clinically actionable mutations in breast cancer patients, and provides provisional data supporting the investigation of RET signaling as a potentially targetable mediator of breast cancer brain metastasis

Exploration of bacterial community classes in major human habitats

BACKGROUND: Determining bacterial abundance variation is the first step in understanding bacterial similarity between individuals. Categorization of bacterial communities into groups or community classes is the subsequent step in describing microbial distribution based on abundance patterns. Here, we present an analysis of the groupings of bacterial communities in stool, nasal, skin, vaginal and oral habitats in a healthy cohort of 236 subjects from the Human Microbiome Project. RESULTS: We identify distinct community group patterns in the anterior nares, four skin sites, and vagina at the genus level. We also confirm three enterotypes previously identified in stools. We identify two clusters with low silhouette values in most oral sites, in which bacterial communities are more homogeneous. Subjects sharing a community class in one habitat do not necessarily share a community class in another, except in the three vaginal sites and the symmetric habitats of the left and right retroauricular creases. Demographic factors, including gender, age, and ethnicity, significantly influence community composition in several habitats. Community classes in the vagina, retroauricular crease and stool are stable over approximately 200 days. CONCLUSION: The community composition, association of demographic factors with community classes, and demonstration of community stability deepen our understanding of the variability and dynamics of human microbiomes. This also has significant implications for experimental designs that seek microbial correlations with clinical phenotypes

SUSTAINABLE RIVER ENGINEERING

Sustainable River engineering is an innovative approach that integrates engineering practices with ecological, social, and economic considerations to manage and restore river systems. Unlike traditional methods, which often prioritize infrastructure and short-term solutions, sustainable river engineering emphasizes resilience, biodiversity, and the preservation of natural processes. This approach involves using eco-friendly materials, restoring natural hydrological patterns, and implementing adaptive management strategies to address challenges such as flooding, erosion, habitat loss, and water quality degradation. By balancing human needs with environmental sustainability, sustainable river engineering promotes long-term benefits, including enhanced ecosystem health, improved water management, and reduced vulnerability to climate change. This abstract explores the principles, materials, and applications of sustainable river engineering, highlighting its potential to foster harmony between human activities and the natural environment

Genomic variation landscape of the human gut microbiome

While large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the latter is largely unexplored in the human microbiome. We therefore developed a framework for metagenomic variation analysis and applied it to 252 fecal metagenomes of 207 individuals from Europe and North America. Using 7.4 billion reads aligned to 101 reference species, we detected 10.3 million single nucleotide polymorphisms (SNPs), 107,991 short indels, and 1,051 structural variants. The average ratio of non-synonymous to synonymous polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This implies that individual-specific strains are not easily replaced and that an individual might have a unique metagenomic genotype, which may be exploitable for personalized diet or drug intake

Individuality and temporal stability of the human gut microbiome

Introduction: The breakthrough of next generation sequencing-technologies has enabled large-scale studies of natural microbial communities and the 16S rRNA genes have been widely used as a phylogenetic marker to study community structure. However, major limitations of this approach are that neither strain-level resolution nor genomic context of microorganisms can be provided. This information, however, is crucial to answer fundamental questions about the temporal stability and distinctiveness of natural microbial communities.Material and methods: We developed a methodological framework for metagenomic single nucleotide polymorphism (SNP) variation analysis and applied it to publicly available data from 252 human fecal samples from 207 European and North American individuals. We further analyzed samples from 43 healthy subjects that were sampled at least twice over time intervals of up to one year and measured population similarities of dominant gut species.Results: We detected 10.3 million SNPs in 101 species, which nearly amounts to the number identified in more than 1,000 humans.Conclusion: The most striking result was that host-specific strains appear to be retained over long time periods. This indicates that individual-specific strains are not easily exchanged with the environment and furthermore, that an individuals appear to have a unique metagenomic genotype. This, in turn, is linked to implications for human gut physiology, such as the stability of antibiotic resistance potential

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

The blood brain barrier plays an important role in traumatic brain injury, serving at the crossroads of secondary injury and potential therapies. In regards to trauma, this barrier contains an array of cellular and molecular components that protect the central nervous system from derangements in water homeostasis and inflammation. Preclinical and clinical assays have been developed to describe and quantify blood brain barrier permeability in relation to the integrity of these blood brain barrier components and the handling of edema. This review will discuss both preclinical and clinical molecular and imaging techniques that are used to assess blood brain barrier function and recovery following traumatic brain injury