Biology subjects

Ananthanarayanan, A.

Publications and source records attributed to Ananthanarayanan, A..

5 recordsLinked to original sources

bioRxiv2025

Network-Based Kidney Allocation Simulation: Evaluating Organ Matching Strategies in Variable Hospital Networks

Kidney allocation is a complex and high-stakes process shaped by various factors. Although existing simulations have improved our understanding of transplant policies, they often stem from the perspectives of medical urgency and biological compatibility. Hence, they often fail to account for the geographic and structural variability of hospital networks that heavily influence organ distribution. In this paper, we present a modular network-based kidney allocation simulation designed to function as a standardized benchmark to evaluate organ matching strategies in more realistic hospital networks. Our simulation models hospitals as nodes in a dynamic network that incorporates detailed donor-recipient compatibility criteria and provides an intuitive interface for testing custom matching policies. Then, through two case studies, we demonstrate how varying network structures and matching strategies affect patient outcomes, quantified through transplant success rates and the percentage of positive patient outcomes. Through these case studies, we derive results that closely resemble real-world observations and identify clear biological explanations for the observed trends, aligning with established empirical knowledge. Our results highlight the importance of geography-/network-aware benchmarks and allocation strategies and provide a standardized platform for future research on optimizing kidney distribution in healthcare networks.

synthetic biology↗

bioRxiv2025

Coordinated macrophage and T cell interactions mediate response to checkpoint blockade in colorectal cancer.

Mismatch repair deficiency (MMRd), either due to inherited or somatic mutation, is prevalent in colorectal cancer (CRC) and other cancers. While anti-PD-1 therapy is utilized in both local and advanced disease, up to 50% of MMRd CRC fail to respond. Using animal and human models of MMRd, we determined that interactions between MHC+ C1Q+ CXCL9+ macrophages and TCF+ BHLHE40+ PRF1+ T cell subsets are associated with control of MMRd tumor growth, during anti-PD-1 treatment. In contrast, resistance is associated with upregulation of TIM3, LAG3, TIGIT, and PD-1 expression on T cells, and infiltration of the tumor with immunosuppressive TREM2+ macrophages and monocytes. By combining anti-PD-1 with anti-LAG3/CTLA4/TREM2, up to 100% tumor eradication was achieved in MMRd CRC and remarkably, in >70% in MMRp CRC. This study identifies key T cell and macrophage subsets mediating the efficacy of immunotherapy in overcoming immune escape in both MMRd and MMRp CRC settings. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/637954v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1778bd6org.highwire.dtl.DTLVardef@17da4e5org.highwire.dtl.DTLVardef@1d4d1d2org.highwire.dtl.DTLVardef@11b58e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAnti-PD-1 therapy leads to the accumulation and colocalization of MHCI/II+ C1Q+ CXCL9+ macrophages and DCs with TCF+ CCL5+ T cells that have high TCR diversity. C_LIO_LIResistance to anti-PD-1 therapy involves multiple T cell checkpoints, TREM2+ macrophages, IL1B+ TREM1+ monocytes and neutrophils, and IFITM+ tumor cells. C_LIO_LISimultaneous blockade of PD-1, LAG3, CTLA-4 and TREM2 dramatically prevents progression of both MMRd and MMRp tumors. C_LIO_LICombination therapy completely eliminates tumors by leveraging MHC+ macrophage, CD4+ and CD8+ T cell interactions, facilitating durable anti-tumor effects. C_LI

immunology↗

bioRxiv2024

Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-{beta} and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/591366v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@18ff2faorg.highwire.dtl.DTLVardef@1991cb6org.highwire.dtl.DTLVardef@12c1a94org.highwire.dtl.DTLVardef@84f87b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Gut bacteria-derived serotonin promotes immune tolerance in early life

The gut microbiome promotes immune system development in early life, but the neonatal gut metabolome remains undefined. Here, we demonstrate that, distinct from adults, the neonatal mouse gut is enriched with neurotransmitters, and specific bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin inhibits mTOR activation to promote regulatory T cells and suppress T cell responses both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term immune tolerance toward both dietary antigens and commensal bacteria as well as alterations of the gut microbiome. Together, our study has uncovered unique microbiome-dependent mechanisms to maximize serotonin in the neonatal gut and a novel role for intestinal serotonin to promote immune tolerance in early life.

immunology↗

bioRxiv2018

Complex Interplay between Serum and Fibroblasts in 3D Hepatocyte Co-culture

Previous studies have suggested that primary hepatocytes cultured in vitro undergo a rapid loss of function. On the other hand, in the clinic, drug induced liver injury typically manifests 5 days to 3 months after starting a medication. Thus, novel approaches that can maintain the function of primary human hepatocytes for longer durations of time may enable the development of improved in vitro assays for detecting hepatotoxicity. Previous studies have demonstrated that two-dimensional micro-patterning of hepatocytes with fibroblasts leads to improved maintenance of the hepatocyte phenotype relative to hepatocyte monocultures, in serum containing medium. Additionally, we, and others, have shown that three-dimensional culture of hepatocytes leads to enhanced function (in serum-free medium). In this study we wanted to (i) examine the effect of combining the above two approaches on hepatocyte function, and (ii) to further delineate the effect of serum on hepatocyte function. We developed a user-friendly and inexpensive approach for constructing layered spheroids. Similar to previous results in two-dimensional (2d) culture, we observed that 3d culture of hepatocytes alone (i.e. monoculture) in serum-containing medium led to an increase in the urea production rate, but near-complete loss of cytochrome activity in both lots of primary human hepatocytes (PHH) tested. In serum-free sandwich culture, cytochrome activity was maintained at the level observed in freshly thawed PHH for one lot, but almost completely lost in another lot. Spheroid culture of both lots of PHH in serum-free medium led to maintenance of CYP3A4 and CYP1A2 activity at the fresh thaw level, though CYP2B6 activity was reduced. In contrast to PHH monoculture, co-cultures of PHH with NIH 3T3 fibroblast cells benefitted from the presence of serum, and led to 3-5-fold increases in CYP activity relative to even serum-free spheroid monocultures. Layering of the fibroblasts did not result in improvements over mixed co-cultures. These results indicate the importance of appropriate serum-free monoculture control experiments in the evaluation of novel biomaterials and techniques for hepatocyte co-culture. Further, urea production and cytochrome production are decoupled; therefore, urea production is an insufficient readout when developing models for pharmaceutical applications.

cell biology↗