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A Rare Case: Dental Panoramic Radiograph Leads to the Diagnosis of a Large Internal Carotid Artery Aneurysm
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Facilitating Living Kidney Donation: Retrospective Evaluation of Weight Loss Interventions to Support Kidney Donation
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Presentation and Management of Pinch-off Syndrome: A Rare Complication of Subclavian Venous Catheters
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Staphylococcus aureus Encodes Multiple Arginine Transporters
No full textStaphylococcus aureus (S. aureus) is the most common pathogen associated with skin and soft tissue infections (SSTI), costing Americans over $13 billion per year. To successfully establish a SSTI, glycolytic activity is required, indicating carbon catabolite repression (CCR) via CcpA is active. CcpA represses secondary carbon sources such as amino acids to ensure the preferential utilization of glucose. This is observed during growth in chemically defined medium with glucose (CDMG), where S. aureus requires supplementation with arginine, since CcpA represses arginine biosynthesis and renders the bacteria auxotrophic for arginine. Therefore, during the establishment of an infection S. aureus relies on the transport of arginine. The S. aureus USA300 genome harbors two arginine/ornithine antiporters, ArcD1 and ArcD2, localized to distinct copies of the arginine deaminase operons. In these studies, inactivation of both transporters did not impair growth, demonstrating they are not required for utilizing arginine as a carbon source. To identify novel arginine transporters, ArgT, we performed a suppressor screen using the toxic arginine analog, canavanine. A radiolabeled transport assay verified ArgT transports arginine, however qRT-PCR indicated the gene is repressed in the presence of glucose by CcpA. These results suggest ArgT is not responsible for the transport of arginine during the establishment of an infection when glucose is present, therefore additional library screens were performed. Growth of mutants from the Nebraska Transposon Mutant Library (NMTL) were analyzed in media supplemented with or without glucose, under conditions dependent on the transport of arginine, or the arginine precursors citrulline and ornithine. Additionally, RNA sequencing was utilized to reveal permease transcripts that were induced under conditions when arginine transport was essential for growth. These methods identified GlnPQ, SAUSA300_2265, SAUSA300_1231, SAUSA300_1642, and SAUSA300_1628 as potential arginine transporters. Growth analysis indicates that AhrC regulates additional transporters, with regulation varying across different media conditions. The comprehensive identification of S. aureus arginine transporters will enable insight into the temporal and spatial dynamics of arginine acquisition during infection, contributing to a deeper understanding of the organisms pathogenesis strategies
Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex
No full textMitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection
Mechanistic Insight of Neuropilin-2 Expression during the Progression of Prostate Cancer
No full textAdvanced prostate cancer represents a particularly aggressive and challenging form of prostate cancer (PCa) that shows resistance to both traditional therapies, such as androgen deprivation therapy, and newer treatment modalities like hormone therapies and immunotherapies. For patients diagnosed with advanced stages of PCa, treatment options are limited, and chemotherapy is often the last line of defense. Unfortunately, chemotherapy can severely diminish the quality of life, particularly in older patients, due to its harsh side effects, including fatigue, immune suppression, and overall physical decline. Despite these challenges, researchers and clinicians remain focused on developing more effective and targeted treatments for patients with advanced prostate cancer. One promising area of research centers on Neuropilin-2 (NRP2), a transmembrane protein that has been identified as significantly upregulated during the progression of prostate cancer. Our research has demonstrated a strong correlation between NRP2 expression and the development of resistance to various therapies in advanced PCa. This resistance not only promotes the continued growth and spread of the tumor (metastasis) but also confers a protective effect, making cancer cells more resilient to treatment-induced cell death. Given the critical role NRP2 plays in both tumor progression and therapy resistance, we propose that targeting NRP2 could provide an effective therapeutic strategy for treating advanced prostate cancer. To get an understanding of the expression profile of NRP2 in high-grade prostate tumors, we stained tissue sections from the primary site of patients with high-grade prostate cancer with and without metastasis. Our findings suggested that NRP2 expression level at the primary tumor site could be an important predictor of disease metastasis. Therefore, understanding how this protein is expressed could play a crucial role in developing NRP2-targeted treatment options. To further explore this potential, we have investigated the mechanisms that regulate the expression of NRP2, focusing on how DNA methylation and the activity of the transcription factors Smad3 and Sox2, influence its expression. Through a series of experiments, we have discovered that the methylation status of the NRP2 promoter region along with the binding activity of Smad3, are key determinants of how much NRP2 is expressed. Smad3, an important downstream signaling molecule in the TGF-B pathway, appears to bind directly to regions within the NRP2 promoter, controlling its expression in metastatic castration resistant prostate cancer. In neuroendocrine like prostate cancer, SOX2, a well-known transcription factor involved in stem cell maintenance and cancer development, further enhances NRP2 expression through a mechanism independent of SMAD3. Our proposal aimed to expand on this knowledge by diving deeper into the interactions between Smad3, SOX2 and the NRP2 gene. Specifically, we investigated the binding dynamics of Smad3 together with it’s association with Sox2 at the regulatory regions of NRP2. This helped us better understand how NRP2 expression is controlled at the molecular level. By thus uncovering the precise mechanism of NRP2’s expression in advanced prostate cancer together with it’s expression pattern in patient tissues across various stages of disease progression, we hope to identify NRP2 as a viable target for future therapies, offering new treatment strategies for patients who currently have limited options