Distributed Drug Discovery: Synthesis of Unnatural Amino Acids as Potential Antimalarial Drugs

Through the collaboration of many institutions across the globe, the Distributed Drug Discovery project founded at Indiana University-Purdue University Indianapolis seeks to aid in the development of drugs for the developing world. In response to two antimalarial assay hits, our team at Abilene Christian University has synthesized many unnatural amino acid analogs using resin-based combinatorial chemistry. Proton nuclear magnetic resonance spectroscopy has been used to characterize the compounds and thin layer chromatography to determine purity. All compounds were purified on hypersep cyanosilica columns

Covalent Chemical Capture of Transcriptional Protein-Protein Interactions Using Genetically Incorporated Photo-crosslinking Amino Acids.

Transient and moderate affinity protein-protein interactions (PPIs) play a critical role in the regulation of essential cellular processes including protein folding, ubiquitylation, and transcription. A number of disease states are believed to be the result of aberrations within these protein networks; therefore, a longstanding therapeutic goal has been to design small molecules that can tunably modulate the constituent interactions. However, the discovery of small molecule modulators has been hindered by lack of structural and mechanistic information, in part due to the limitations of the approaches currently available for studying transient PPIs in their native environments. Techniques such as co-crystallization and co-purification in vitro and two-hybrid studies in vivo are best suited for probing stably associated proteins, but are less ideal for studying proteins that engage in modest-affinity and/or transient multi-protein binding interaction. In my thesis, I focus on the in vivo covalent capture of such binding partners of the prototypical activator VP16 using in vivo photocrosslinking with a genetically incorporated photo-labile amino acid. The success of using this methodology for characterizing activator-coactivator complexes in vivo indicates that this strategy can be implemented more broadly for the capture and discovery of transient protein-protein interactions in their native contexts.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/102310/1/duganam_1.pd

Utilizing Service Learning in the Analytical Chemistry Classroom

Service learning has been incorporated into the Analytical Chemistry Laboratory to give students a real world sampling experience including both soil and water, alongside professionals in their fields. Analysis of the soil and water includes metals, suspended solids, phosphorus and nitrogen containing compounds requiring knowledge of several different instrumental and wet chemical techniques. Most educational experiences do not afford students the chance to see the real world applications of their classroom knowledge, but with the service learning aspects this deficiency has been resolved. In the soil experience, students provide homeowners from the Highland Park and South Wedge neighbors with lead analysis of their soil as well as written reports of those levels and information on removing or working with lead contaminated soil. For the water project, students are providing baseline analysis of nutrients and metals found in Buckland Creek for the Department of Environmental Services, Division of Pure Waters, which studies the effects of industrial expansion and human activity on water quality in Rochester. The analytical chemistry students further their experience in an advanced analytical chemistry course the following year by performing further analysis on the soil and water, but on a more independent level. They use their previous learned skills to gather water after rainfall and perform analysis back in the laboratory with no structured guidance. The class is also expanding to include a plant biology section, where students will test the affects on growth and safety of plants grown in leaded soil. This experiment will allow students to provide proof to homeowners as to which plants are healthy to eat and which can be used for phytoremediation. In addition to feeling like active contributors to the community, the students and homeowners have been interviewed and photographed for an article detailing lead contamination issues

Sequence context and crosslinking mechanism affect the efficiency of in vivo capture of a protein–protein interaction

Protein–protein interactions (PPIs) are essential for implementing cellular processes and thus methods for the discovery and study of PPIs are highly desirable. An emerging method for capturing PPIs in their native cellular environment is in vivo covalent chemical capture, a method that uses nonsense suppression to site specifically incorporate photoactivable unnatural amino acids (UAAs) in living cells. However, in one study we found that this method did not capture a PPI for which there was abundant functional evidence, a complex formed between the transcriptional activator Gal4 and its repressor protein Gal80. Here we describe the factors that influence the success of covalent chemical capture and show that the innate reactivity of the two UAAs utilized, ( p‐ benzoylphenylalanine (pBpa) and p ‐azidophenylalanine (pAzpa)), plays a profound role in the capture of Gal80 by Gal4. Based upon these data, guidelines are outlined for the successful use of in vivo photo‐crosslinking to capture novel PPIs and to characterize the interfaces. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 391–397, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102672/1/bip22395.pd

The impact of historical redlining on neurosurgeon distribution and reimbursement in modern neighborhoods

BackgroundThis study examines the lasting impact of historical redlining on contemporary neurosurgical care access, highlighting the need for equitable healthcare in historically marginalized communities.ObjectiveTo investigate how redlining affects neurosurgeon distribution and reimbursement in U.S. neighborhoods, analyzing implications for healthcare access.MethodsAn observational study was conducted using data from the Center for Medicare and Medicaid Services (CMS) National File, Home Owner’s Loan Corporation (HOLC) neighborhood grades, and demographic data to evaluate neurosurgical representation across 91 U.S. cities, categorized by HOLC Grades (A, B, C, D) and gentrification status.ResultsOf the 257 neighborhoods, Grade A, B, C, and D neighborhoods comprised 5.40%, 18.80%, 45.8%, and 30.0% of the sample, respectively. Grade A, B, and C neighborhoods had more White and Asian residents and less Black residents compared to Grade D neighborhoods (p < 0.001). HOLC Grade A (OR = 4.37, 95%CI: 2.08, 9.16, p < 0.001), B (OR = 1.99, 95%CI: 1.18, 3.38, p = 0.011), and C (OR = 2.37, 95%CI: 1.57, 3.59, p < 0.001) neighborhoods were associated with a higher representation of neurosurgeons compared to Grade D neighborhoods. Reimbursement disparities were also apparent: neurosurgeons practicing in HOLC Grade D neighborhoods received significantly lower reimbursements than those in Grade A neighborhoods ($109,163.77 vs.$142,999.88, p < 0.001), Grade B neighborhoods ($109,163.77 vs.$131,459.02, p < 0.001), and Grade C neighborhoods ($109,163.77 vs.$129,070.733, p < 0.001).ConclusionHistorical redlining continues to shape access to highly specialized healthcare such as neurosurgery. Efforts to address these disparities must consider historical context and strive to achieve more equitable access to specialized care

Influenza Activity and Composition of the 2022-23 Influenza Vaccine - United States, 2021-22 Season

Before the emergence of SARS-CoV-2, the virus that causes COVID-19, influenza activity in the United States typically began to increase in the fall and peaked in February. During the 2021-22 season, influenza activity began to increase in November and remained elevated until mid-June, featuring two distinct waves, with A(H3N2) viruses predominating for the entire season. This report summarizes influenza activity during October 3, 2021-June 11, 2022, in the United States and describes the composition of the Northern Hemisphere 2022-23 influenza vaccine. Although influenza activity is decreasing and circulation during summer is typically low, remaining vigilant for influenza infections, performing testing for seasonal influenza viruses, and monitoring for novel influenza A virus infections are important. An outbreak of highly pathogenic avian influenza A(H5N1) is ongoing; health care providers and persons with exposure to sick or infected birds should remain vigilant for onset of symptoms consistent with influenza. Receiving a seasonal influenza vaccine each year remains the best way to protect against seasonal influenza and its potentially severe consequences

The Lantern, 2011-2012

• Frangipani • A Shadow • Dear Anne, In this Place, Stringbean Girls • Back to a Dandelion • How to Plant a Room • Swimming Pool Poem 30 • The Naming of Daughters • Berman Museum Photographs • Truth or Dare • The Song of Remembrance, L\u27vov, Poland, 1940 • Headlights • Prayer of Thanks • Numbers Game • Pediment • Home Sick • Lust • Sand Lining Instructions • A-A-Ask a Question • Flash Cards • Columbus Day • Mr. Yoest Gives His Report to the Police Officers on Wednesday Night • Gender Trouble • The Internet Connection at Ursinus College • Assuming You\u27ll Still be Here • 10/28/11, Third Poem • October • Actions that Affirm and Confirm Us as a Community • Why I Hate The Lantern • Confessions of an Ex-Vegetarian • Run • Lunch at Caltort • Schemers • You Will Make Beautiful Babies in America • The Black Dirt Region • Il Travatore • Ghost Story • Blue Eyes and Sunny Skies • A Little Sincerity • The Bookstore • The Opposite of Serendipity • The Human Doll • Evil Deeds • Francesca • Sunday Morning • Jersey Aesthetic • Jump! • Behind Reimert • Seaweed in New Zealand • Tombee de L\u27elegance • The Window • Esperando • Rainbow to the Heavens • Encased • In Springtime • A Fiesolan Monk\u27s Room • Inside a Bone • Neon Indian • Moments of Clarity • OneFeral: A Feral Self-Portrait • Cover Image: The Conquerorhttps://digitalcommons.ursinus.edu/lantern/1177/thumbnail.jp

The whole genome sequence of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), reveals insights into the biology and adaptive evolution of a highly invasive pest species

The Mediterranean fruit fly (medfly), Ceratitis capitata, is a major destructive insect pest due to its broad host range, which includes hundreds of fruits and vegetables. It exhibits a unique ability to invade and adapt to ecological niches throughout tropical and subtropical regions of the world, though medfly infestations have been prevented and controlled by the sterile insect technique (SIT) as part of integrated pest management programs (IPMs). The genetic analysis and manipulation of medfly has been subject to intensive study in an effort to improve SIT efficacy and other aspects of IPM control

IL-6 Mediated Degeneration of Forebrain GABAergic Interneurons and Cognitive Impairment in Aged Mice through Activation of Neuronal NADPH Oxidase

BACKGROUND:Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. METHODS AND FINDINGS:We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6(-/-) mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFkappaB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. CONCLUSIONS:Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically

Genome of the Asian Longhorned Beetle (\u3cem\u3eAnoplophora glabripennis\u3c/em\u3e), a Globally Significant Invasive Species, Reveals Key Functional and Evolutionary Innovations at the Beetle-Plant Interface

Background: Relatively little is known about the genomic basis and evolution of wood-feeding in beetles. We undertook genome sequencing and annotation, gene expression assays, studies of plant cell wall degrading enzymes, and other functional and comparative studies of the Asian longhorned beetle, Anoplophora glabripennis, a globally significant invasive species capable of inflicting severe feeding damage on many important tree species. Complementary studies of genes encoding enzymes involved in digestion of woody plant tissues or detoxification of plant allelochemicals were undertaken with the genomes of 14 additional insects, including the newly sequenced emerald ash borer and bull-headed dung beetle. Results: The Asian longhorned beetle genome encodes a uniquely diverse arsenal of enzymes that can degrade the main polysaccharide networks in plant cell walls, detoxify plant allelochemicals, and otherwise facilitate feeding on woody plants. It has the metabolic plasticity needed to feed on diverse plant species, contributing to its highly invasive nature. Large expansions of chemosensory genes involved in the reception of pheromones and plant kairomones are consistent with the complexity of chemical cues it uses to find host plants and mates. Conclusions: Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle, certain other phytophagous beetles, and to a lesser degree, other phytophagous insects. Our results thus begin to establish a genomic basis for the evolutionary success of beetles on plants