The synthesis, structural characterization and biological evaluation of potential chemotherapeutic agents

Cathepsin proteases have been identified in many parasitic organisms and are involved in roles as diverse as tissue and skin penetration, virulence and immune invasion. Involvement in these key functions renders them potential targets at which to direct novel chemotherapeutic agents. The inhibitor N-benzoyl-L-Leu-Gly nitrile prepared in this laboratory was shown to possess significantly greater inhibitory potency on the liver fluke Fasciola hepatica cysteine cathepsin L like endoproteases over the known commercial inhibitor Z-Phe-Ala-CHN₂ at varying concentrations. The synthesis, structural characterisation and biological evaluation of a series of analogues of this active compound is now reported. Addition of fluorine atoms to the N-terminal benzoyl group and selective modification of the N-terminus is reported. These dipeptidyl derivatives were synthesized using the standard DCC/HOBt or EDC/HOBt protocols. These novel Cathepsin L inhibitors have been characterized by a wide range of spectroscopic techniques including ¹H, ¹³C, ¹⁹F NMR and ESIMS. The biological activity of these novel compounds was determined in a bioassay using Z-Phe-Arg-NHMec as a fluorogenic substrate. Resveratrol is a naturally occurring phyloalexin found in several plants but mainly in the skins of grapes. It has been shown to be produced in response to bacterial and fungal infections. It has been shown to exhibit various biological activities including anticancer, antifungal, antiviral, neuroprotective, anti-aging, and anti-inflammatory effects. The synthesis of fluorinated stilbenes containing the 3,5,4'-substituted backbone was accomplished. The compounds were synthesised via the Wittig reaction and the decarbonylative Heck reaction. In conjunction with fluorine, nitrogen was also used as a replacement for the oxygen atoms of the resveratrol structure. Full structural characterisation of these compounds was carried out followed by preliminary biological screening

Composition of dissolved organic matter within a lacustrine environment

Freshwater dissolved organic matter (DOM) is a complex mixture of chemical components that are central to many environmental processes, including carbon and nitrogen cycling. However, questions remain as to its chemical characteristics, sources and transformation mechanisms. Here, we employ 1- and 2-D nuclear magnetic resonance (NMR) spectroscopy to investigate the structural components of lacustrine DOM from Ireland, and how it varies within a lake system, as well as to assess potential sources. Major components found, such as carboxyl-rich alicyclic molecules (CRAM) are consistent with those recently identified in marine and freshwater DOM. Lignin-type markers and protein/peptides were identified and vary spatially. Phenylalanine was detected in lake areas influenced by agriculture, whereas it is not detectable where zebra mussels are prominent. The presence of peptidoglycan, lipoproteins, large polymeric carbo- hydrates and proteinaceous material supports the substantial contribution of material derived from microorganisms. Evidence is provided that peptidoglycan and silicate species may in part originate from soil microbes

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia

Unconstrained Submodular Maximization with Constant Adaptive Complexity

In this paper, we consider the unconstrained submodular maximization problem. We propose the first algorithm for this problem that achieves a tight $(1/2-\varepsilon)$-approximation guarantee using $\tilde{O}(\varepsilon^{-1})$ adaptive rounds and a linear number of function evaluations. No previously known algorithm for this problem achieves an approximation ratio better than $1/3$ using less than $\Omega(n)$ rounds of adaptivity, where $n$ is the size of the ground set. Moreover, our algorithm easily extends to the maximization of a non-negative continuous DR-submodular function subject to a box constraint and achieves a tight $(1/2-\varepsilon)$-approximation guarantee for this problem while keeping the same adaptive and query complexities.Comment: Authors are listed in alphabetical orde

Institutional Transplant as Political Opportunity: The Practice and Politics of Indian Electricity Regulation

India has a decade-long experience with independent regulatory agencies in public services as an institutional transplant from the industrialized world. Introduced at the behest of international donor agencies, regulators in India are intended, somewhat naively, to provide an apolitical space for decision making to assuage investor concerns over arbitrary administrative actions, and thereby stimulate private investment. In practice, regulators have had to negotiate a terrain over which the state has continued to exercise considerable control. Regulators have also been been shaped in their functioning by national and sub-national political traditions and by administrative and political practices. The result is a hybrid institutional form that combines politics as usual with intriguing new, and unanticipated, opportunities for political intervention. This paper will explore the origins of electricity regulation as a form of institutional isomorphism. It will then compare the regulatory experience in India\u27s electricity sector across two Indian states to understand the implications of transplanting regulatory agencies in the global south. An examination of the process through which regulatory decisions are reached illustrates how existing bureaucratic and technocratic networks, transplanted procedures, and administrative cultures combine to conservatively manage long-standing political tensions around electricity. In seeking to manage those tensions, regulators often take decisions - on tariff setting, for example - based on a political reading that belies the technocratic narrative on which institutional credibility rests. At the same time, civil society groups ranging from residential associations to professional associations to individuals are using newly created regulatory spaces to structure a more deliberative decision process

Beryllium isotopes in central Arctic Ocean sediments over the past 12.3 million years: Stratigraphic and paleoclimatic implications

The upper 200 m of the sediments recovered during IODP Leg 302, the Arctic Coring Expedition (ACEX), to the Lomonosov Ridge in the central Arctic Ocean consist almost exclusively of detrital material. The scarcity of biostratigraphic markers severely complicates the establishment of a reliable chronostratigraphic framework for these sediments, which contain the first continuous record of the Neogene environmental and climatic evolution of the Arctic region. Here we present profiles of cosmogenic 10Be together with the seawater-derived fraction of stable 9Be obtained from the ACEX cores. The down-core decrease of 10Be/9Be provides an average sedimentation rate of 14.5 ± 1 m/Ma for the uppermost 151 m of the ACEX record and allows the establishment of a chronostratigraphy for the past 12.3 Ma. The age-corrected 10Be concentrations and 10Be/9Be ratios suggest the existence of an essentially continuous sea ice cover over the past 12.3 Ma

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment