Design, Synthesis, and Biological Evaluation of Folate Targeted Photosensitizers for Photodynamic Therapy

Photodynamic therapy (PDT) is used to treat cancer, and involves a highly conjugated molecule, called a photosensitizer (PS), which is excited by wavelengths of light from visible to infrared. Photosensitizers that are highly conjugated will absorb longer wavelengths (600 – 900 nm), and have the potential to destroy cells of deeper tissue cancers. In PDT, a PS is administered to the patient, and after an appropriate time delay, the tissue is then exposed to light of a specific wavelength necessary for excitation of the PS. A transfer of energy can take place between the excited PS and oxygen that is nearby. This process allows the PS to relax back to the ground state, while creating an excited singlet state oxygen molecule (1O2). Buchwald-Hartwig conditions using Pd catalysts and phosphorus containing ligands can be utilized to synthesize the photosensitizer. The reaction involves a Pd-catalyzed cross coupling of an aryl halide with a nitrogen nucleophile to form a new carbon-nitrogen bond. The PS will be PEGylated with an amine–PEG–Folate complex. Since many tumors over-express folate receptors, the PS–PEG–FA complex will be transported to cancer cells via receptor mediated endocytosis, providing greater selectivity. The killing efficiency of the PS will be tested using HeLa cells. Solutions containing PS only, PS–PEG–FA, and media only will be added to cancer cells with folate restricted media. After exposure to light, the cells will be counted to determine the percentage of cells killed by the singlet oxygen and other radical species. Variables that must be controlled in this study are the following: length of time cells have been growing; specific concentration of PS–PEG–folate complex; length of time for PS–PEG–folate complex uptake into the cell; length of time of exposure to light; length of time from light exposure to cell counting to determine necrosis. The goal of the research is to determine the concentration of PS and length of time of light exposure that is maximally effective for killing tumor cells

Defining the Environmental Niche of the Two Main Clades of \u3ci\u3eTrichodesmium\u3c/i\u3e: A Study on the West Florida Shelf

Dinitrogen (N2) fixation is the process of taking widely abundant but mostly biologically inaccessible N2 gas and converting it into more biologically accessible forms of the essential macronutrient nitrogen. Only a small fraction of organisms known as diazotrophs can perform biological N2 fixation. Trichodesmium is one such genus of N2-fixing marine cyanobacteria that is commonly observed in waters along the West Florida Shelf (WFS). We hypothesize that the two main Trichodesmium clades (T. erythraeum and T. thiebautii) occupy distinct environmental niches, one being more coastal and one being more oceanic. To test this hypothesis, we quantified gene abundance of both clades and compared the results with hydrographic data to distinguish any trends in niche distribution in samples collected on the WFS from three separate cruises. T. thiebautii abundance was higher further from the coast (at stations with greater bottom depths) and the T. erythraeum abundance was higher closer to the coast (at stations with lower bottom depths). A lack of nearshore sampling in 2015 initially made it difficult to conclusively identify trends in niche distribution, however with the addition of 2018 and 2019 samples, we observed a consistent coastal vs. open ocean niche separation for the two clades. In addition, T.thiebautii abundance was also significantly positively correlated with salinity. While previous work has found T. thiebautii is more abundant than T. erythraeum in open ocean surface waters, this is the first study to examine Trichodesmium clade abundance in a near-shore environment.https://digitalcommons.odu.edu/gradposters2021_sciences/1010/thumbnail.jp

Infrared Emission from the Nearby Cool Core Cluster Abell 2597

We observed the brightest central galaxy (BCG) in the nearby (z=0.0821) cool core galaxy cluster Abell 2597 with the IRAC and MIPS instruments on board the Spitzer Space Telescope. The BCG was clearly detected in all Spitzer bandpasses, including the 70 and 160 micron wavebands. We report aperture photometry of the BCG. The spectral energy distribution exhibits a clear excess in the FIR over a Rayleigh-Jeans stellar tail, indicating a star formation rate of ~4-5 solar masses per year, consistent with the estimates from the UV and its H-alpha luminosity. This large FIR luminosity is consistent with that of a starburst or a Luminous Infrared Galaxy (LIRG), but together with a very massive and old population of stars that dominate the energy output of the galaxy. If the dust is at one temperature, the ratio of 70 to 160 micron fluxes indicate that the dust emitting mid-IR in this source is somewhat hotter than the dust emitting mid-IR in two BCGs at higher-redshift (z~0.2-0.3) and higher FIR luminosities observed earlier by Spitzer, in clusters Abell 1835 and Zwicky 3146.Comment: Accepted at Ap

Association of Irritability and Anxiety With the Neural Mechanisms of Implicit Face Emotion Processing in Youths With Psychopathology

Importance: Psychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology. Objective: To determine shared and unique effects of 2 major dimensions of child psychopathology, irritability and anxiety, on neural responses to facial emotions during functional magnetic resonance imaging. Design, Setting, and Participants: Cross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths. Main Outcomes and Measures: The child's irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions. Results: The mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F4,888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald χ21 = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F2, 888 ≥ 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces. Conclusions and Relevance: These data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala-medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth

Defining the Realized Niche of the Two Major Clades of \u3ci\u3eTrichodesmium\u3c/i\u3e: A Study on the West Florida Shelf

The cyanobacterium Trichodesmium plays an essential role supporting ocean productivity by relieving nitrogen limitation via dinitrogen (N-2) fixation. The two common Trichodesmium clades, T. erythraeum and T. thiebautii, are both observed in waters along the West Florida Shelf (WFS). We hypothesized that these taxa occupy distinct realized niches, where T. thiebautii is the more oceanic clade. Samples for DNA and water chemistry analyses were collected on three separate WFS expeditions (2015, 2018, and 2019) spanning multiple seasons; abundances of the single copy housekeeping gene rnpB from both clades were enumerated via quantitative PCR. We conducted a suite of statistical analyses to assess Trichodesmium clade abundances in the context of the physicochemical data. We observed a consistent coastal vs. open ocean separation of the two clades: T. erythraeum was found in shallow waters where the concentrations of dissolved iron (dFe) and the groundwater tracer Ba were significantly higher, while T. thiebautii abundance was positively correlated with water column depth. The Loop Current intrusion in 2015 with entrained Missisippi River water brought higher dFe and elevated abundance of both clades offshore of the 50 m isobath, suggesting that both clades are subject to Fe limitation on the outer shelf. Whereas, previous work has observed that T. thiebautii is more abundant than T. erythraeum in open ocean surface waters, this is the first study to examine Trichodesmium niche differentiation in a coastal environment. Understanding the environmental niches of these two key taxa bears important implications for their contributions to global nitrogen and carbon cycling and their response to global climate change

How is neighborhood social disorganization associated with diabetes outcomes? A multilevel investigation of glycemic control and self-reported use of acute or emergency health care services

Abstract Background Diabetes management is influenced by a number of factors beyond the individual-level. This study examined how neighborhood social disorganization (i.e., neighborhoods characterized by high economic disadvantage, residential instability, and ethnic heterogeneity), is associated with diabetes-related outcomes. Methods We used a multilevel modeling approach to investigate the associations between census-tract neighborhood social disorganization, A1c, and self-reported use of acute or emergency health care services for a sample of 424 adults with type 2 diabetes. Results Individuals living in neighborhoods with high social disorganization had higher A1c values than individuals living in neighborhoods with medium social disorganization (B = 0.39, p = 0.01). Individuals living in neighborhoods with high economic disadvantage had higher self-reported use of acute or emergency health care services than individuals living in neighborhoods with medium economic disadvantage (B = 0.60, p = 0.02). Conclusions High neighborhood social disorganization was associated with higher A1c values and high neighborhood economic disadvantage was associated with greater self-reported use of acute or emergency health care services. Controlling for individual level variables diminished this effect for A1c, but not acute or emergency health care use. Comprehensive approaches to diabetes management should include attention to neighborhood context. Failure to do so may help explain the continuing disproportionate diabetes burden in many neighborhoods despite decades of attention to individual-level clinical care and education. Trial registration For this study, we used baseline data from a larger study investigating the impacts on patient-centered outcomes of three different approaches to self-monitoring of blood glucose among 450 adults with non-insulin dependent type 2 diabetes living in North Carolina. This study was registered as a clinical trial on 1/7/2014 ( https://clinicaltrials.gov/ct2/show/NCT02033499 )

A melanocyte lineage program confers resistance to MAP kinase pathway inhibition

BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAPK) signaling for tumor cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma2, 3; however, resistance to these agents remains a formidable challenge2, 4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here, we performed systematic gain-of-function resistance studies by expressing >15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAFV600E melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAP kinase pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics

Bridgewater “Comments” on 80 Years of Men’s and Women’s Sports

Sports media is important because it shapes the perceptions, aspirations and dreams of the viewers (Angelini, 2008). It shows the viewers the skill and athletic achievement of both male and female athletes. The media allows viewers to witness the athletic prowess of their favorite athletes on TV and in print. Within sports media, the viewers are able to learn about the many different sports that are offered around the world. The viewers are able to get a sense about who the athletes are, their talents, their sport and their achievement. It is apparent that sports media has a huge impact on the people around the world who watch games, buy magazines, and endorse their favorite team by collecting team and player memorabilia