Defining the Role of Neuropilin-2 in Macrophages: Implications in Tumor Associated Macrophages in Pancreatic Cancer

Macrophages are extremely heterogeneous and highly plastic hematopoietic cells that reside in all tissues and act as a bridge between the innate and adaptive arms of the immune responses. Besides, they undertake a wide array of housekeeping functions like, clearance of cellular debris that arise due to regular turnover in tissues, iron homeostasis, immune surveillance as well as tissue repair processes post inflammation. They are also causally associated with several clinical conditions, including cancer where the infiltration of macrophages contribute to disease progression, metastasis and therapy resistance, and thereby poor clinical outcome. Neuropilins (NRPs) are non-tyrosine kinase cell surface glycoproteins expressed in all vertebrates and widely conserved across species. The two isoforms, NRP1 and NRP2 are mainly known for their role as co-receptors for class III Semaphorins and for members of the vascular endothelial growth factor (VEGF) family of molecules. Both NRP1 and NRP2 are overexpressed in many cancers, exert pleiotropic effects in various aspects of cancer pathobiology and correlate with the stage and grade of the disease and poor survival. Intriguingly, additional immunoregulatory roles for NRPs have been reported in myeloid and lymphoid cells, in normal physiological as well as different pathological conditions, including cancer, various immunological disorders, and bone diseases. In comparison to NRP1, the overall comprehensive function of NRP2 in macrophages and factors that govern those functions is not well known. Therefore, the enveloping goal of this dissertation is to comprehensively understand the role and function of NRP2 in macrophages and their implication in tumor associated macrophages in solid tumor. In the first part of the dissertation, we primarily investigated the expression pattern of NRP2 during the differentiation of macrophages under inflammatory (M1) and immunosuppressive (M2) polarizing conditions. We observed although NRP2 is not expressed at a detectable level in monocytes, its expression is upregulated during the differentiation of monocytes precursors to either M1 or M2 type mature macrophages. We identified a novel function of NRP2 in regulating phagocytosis in macrophages by modulating the levels of Rab5+ early phagosomes and Rab7+ late phagosomes. In NRP2 depleted macrophages clearance of bacteria or yeast components was delayed and these cells exhibited elevated number or early phagosomes and decreased number of late phagosomes. Since pancreatic cancer (PC) typifies the complex architecture of a tumor stroma and tumor associated macrophages are abundantly present here, the second part of the dissertation is aimed at elucidating the implication of NRP2 regulated phagocytosis in TAMs in this lethal disease. The expression NRP2 in TAMs in human and mouse PC tissues was assessed. Due to nutrient limiting conditions and rapid proliferation of tumor cells in the TME, many of the cancer cells undergo apoptosis. TAMs efferocytose these dying tumor cells, an event that polarizes them further to pro-tumoral type and contribute to relapse and therapy resistance. We observed that in the absence of NRP2, clearance of apoptotic cells was delayed. The implication of this observation in PC progression was tested using a subcutaneous tumor model. Upon depletion of NRP2 in TAMs, tumors were smaller. Of note, NRP2 depletion did not affect TAM recruitment to, or angiogenesis but recruited and activated anti-tumor CD8 cells into the TME. Further, RNA-Seq analysis of CD11b+ TAMs isolated from tumors indicated that many genes associated with either endosomal/phagosomal maturation, recycling and exocytosis, immune modulation and leukocyte recruitment and activation are deregulated following NRP2 depletion. Further, NRP2 depletion downregulated many of the immunosuppressive genes and cytokines in macrophages that may be important for either suppression of T cell response or induce Treg formation. The data further suggested that NRP2 is important for efferocytosis and maintaining TAM-like phenotype in intratumoral macrophages, thus helping to create a tumorigenic immunosuppressive environment in the TME. Taken together, studies in this dissertation document a requirement for NRP2 in macrophage phagocytosis. Further, regulation of efferocytosis in TAMs by NRP2 have implications in TAM functions and tumor progression. Hence, targeting NRP2 axis in TAMs may help re-engineer the immunosuppressive stroma in the TME and emerge as potential therapy in combination with chemotherapy or other adjuvant therapies

Bisphenol A: Understanding Its Health Effects from the Studies Performed on Model Organisms

Bisphenol A [4,4′‐(propane‐2,2‐diyl)diphenol] (abbreviated as BPA) is a synthetic xenoestrogenic chemical and endocrine disruptor. It is a most common plasticizer that is used widely to produce epoxy resin and polycarbonate plastics, enters the living system through food and water contamination and generates health hazards. Researches are being conducted to explore the adversity that BPA exerts in living body, and for this reason, model organisms are of scientific choice. Rodents, zebrafish, Drosophila, nematodes, crustaceans and echinoderms are being used for monitoring the effect of BPA on their life history traits, nervous system, endocrine system, reproductive systems, behaviour, etc., which could help us to anticipate what kind of challenges BPA is putting in human life. This systematic review is focused on the latest research trend on BPA toxicity on different model organisms

Single cell fertilizer (SCF): Evidence to prove that bio-molecules are potent nutrient for plant growth

Fertilizers of various kinds are used for the cultivation of crop plants for hyper production of plant based food materials. The study used bio-molecules made in a bacterial cell. The experimental results showed tremendous effect on plant growth. These cellular molecules were made by treating the bacterial cells with lysozyme and protenase K. The wet/weight was increased in multiple folds compared to that of control sets. The fold of increase was 4.79 for rice, 2.77 for wheat, 1.89 for gram and 1.89 for pea when bacterial cellular molecules were used as fertilizer

NRP2 transcriptionally regulates its downstream effector WDFY1.

Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)-protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, essential for promotion of oncogenic activation and cancer cell survival. Here, we have delineated the underlying molecular mechanism of WDFY1 synthesis by NRP2. Our results indicated that NRP2 inhibits WDFY1 transcription by preventing the nuclear localization of a transcription factor, Fetal ALZ50-reactive clone 1 (FAC1). Our finding is novel as transcriptional regulation of a gene by NRP2 axis has not been reported previously. Regulation of WDFY1 transcription by NRP2 axis is a critical event in maintaining metastatic phenotype in cancer cells. Thus, inhibiting NRP2 or hyper-activating WDFY1 can be an effective strategy to induce cell death in metastatic cancer

Machine Learning Models for Road Surface and Friction Estimation using Front-Camera Images

Automotive active safety systems can significantlybenefit from real-time road friction estimates (RFE) by adaptingdriving styles, specific to the road conditions. This work presentsa 2-stage approach for indirect RFE estimation using front-viewcamera images captured from vehicles. In stage-1, convolutionalneural network model architectures are implemented to learnregion-specific features for road surface condition (RSC) classification.Texture-based features from the drivable surface, skyand surroundings are found to be separate regions of interest fordry, wet/water, slush and snow/ice RSC classification. In stage-2, a rule-based model that relies on domain-specific guidelinesis implemented to segment the ego-lane drivable surface into[5x3] patches, followed by patch classification and quantization toseparate images with high, medium and low RFE. The proposedmethod achieves average accuracy of 97% for RSC classificationin stage-1 and 89% for RFE classification in stage-2, respectively.The 2-stage models are trained using publicly available datasets to enable benchmarkin

A study to assess the level of knowledge regarding prevention and management of acute respiratory infection among mothers of children 0-5 years in selected hospital in Siliguri

Background: In developing countries like India acute respiratory infection (ARI) contributes in child mortality upto 75% and out of 10, 7 deaths are due to ARI. The knowledge of the mothers towards the disease is a significant determinant of child’s health.Methods: A descriptive cross-sectional study included 100 mothers of children 0-5 years admitted in pediatric ward and postnatal ward in selected hospital Siliguri during the year 2022 in the month of March. Data was collected using structured interview method.Results: 20% of mothers have good knowledge in prevention and 33% had good knowledge in management of ARI.Conclusions: As the leading cause of death among children, knowledge assessment about ARI among the mothers is very important, which helps for better understanding of the intensity of the problem