A target repurposing approach identifies N-myristoyltransferase as a new candidate drug target in filarial nematodes

Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5-10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis

Ophthalmoplegic Migraine and Infundibular Dilatation of a Cerebral Artery

Ophthalmoplegic migraine (OM) is a childhood disorder of uncertain etiology manifesting recurrent unilateral headache associated with a transitory oculomotor (usually IIIrd nerve) palsy. Recent publications emphasize the finding on MRI of contrast enhancement in the IIIrd nerve suggesting that OM may be a recurrent inflammatory neuropathy. We report the case of a 7-year-old boy with typical symptoms of this disorder. Angio MR and Angio CT revealed the presence of an infundibular dilatation of a perforating branch of the posterior cerebral artery adjacent to the symptomatic IIIrd nerve. We speculate that this and perhaps other cases of OM may have a different pathophysiology related to compression of the IIIrd nerve by an adjacent vascular structure that could activate the trigeminovascular system and produce migrainous pain

Kragen v. Dist. Ct., 140 Nev. Adv. Op. 49 (Aug. 15, 2024)

The Nevada Court of Appeals held that, when evaluating appropriate home state jurisdiction in child custody disputes, the temporary or permanent nature of a child’s absence from the state must be assessed in light of the totality of the circumstances. By adopting the totality of the circumstances test, Nevada has fallen in line with a majority of states that have implemented the Uniform Child Custody Jurisdiction and Enforcement Act (“UCCJEA”)

[Re]Forming Public Space: A Critique of Hong Kong’s Park Governance through Architectural Intervention

This paper’s point of departure is a critique of the Hong Kong government’s somewhat rigid approach to regulating the public spaces of its parks. As an antidote to a rule-bound and somewhat restrictive set of policies, four groups of architecture students at the University of Hong Kong have designed various interventions for a public park in Hong Kong. The projects, entitled Pixel Wall, Fence Off, Border Mender, and Rocky present alternative ways of activating public space through architectural design

Soldo-Allesio v. Ferguson, 141 Nev. Adv. Op. 9 (Feb. 13, 2025)

The Nevada Court of Appeals held that, when considering domestic violence as part of a best interest factors analysis in a custody determination, the appropriate evidentiary standard is the default preponderance-of-the-evidence standard of family law—not the clear-and-convincing-evidence standard that is used for the domestic violence rebuttable presumption which may lead to the denial of a parent’s custody. Additionally, the Court held that district courts must provide a legal basis for appellate review when excluding trial court exhibits for timeliness, because such exclusions constitute sanctions that must meet the legal standards found in rules like NRCP 16.205(g) and NRCP 37(c)

Weak selection and stability of localized distributions in Ostwald ripening

We support and generalize a weak selection rule predicted recently for the self-similar asymptotics of the distribution function (DF) in the zero-volume-fraction limit of Ostwald ripening (OR). An asymptotic perturbation theory is developed that, when combined with an exact invariance property of the system, yields the selection rule, predicts a power-law convergence towards the selected self-similar DF and agrees well with our numerical simulations for the interface- and diffusion-controlled OR.Comment: 4 pages, 2 figures, submitted to PR

A faunal survey and zoogeographic analysis of the Curculionoidea (Coleoptera) (excluding Anthribidae, Platypodinae, and Scolytinae) of the Lower Rio Grande Valley of Texas

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references: p. 239-257.Issued also on microfiche from Lange Micrographics.An annotated list of the Curculionoidea (Coleoptera) (excluding Anthribidae, Platypodinae, and Scolytinae) is presented for the Lower Rio Grande Valley (LRGV) of Texas. The list includes species that occur in Cameron, Hidalgo, Starr, and Willacy counties. Each of the 235 species in 97 genera is treated according to its geographical range, Lower Rio Grande distribution, seasonal activity, plant associations, and biology. The taxonomic arrangement follows O'Brien & Wibmer (1982). A table of the species occurring in particular areas of the Lower Rio Grande Valley, such as the Boca Chica Beach area, the Sabal Palm Grove Sanctuary, Bentsen-Rio Grande State Park, and the Falcon Dam area is included. A table of the species and their host associations is also presented. Genera (number of species in parentheses) with the largest number of species represented are: Anthoiionzits (12), Apion (13), Conotrachehts (II), Listronotils (17), Sibinia (10), and Siiticronyx (15). Thirty percent of the total species in the Lower Rio Grande Valley belong in these genera. There are 22 undetermined and/or undescribed species recorded. Zoogeographic comparisons are made between the LRGV and Guatemala, North Dakota, Victoria County, San Patricio County, Big Bend National Park, and southern Florida. A high percentage of species of the LRGV were found to have northern affinities. Eight non-native species were not included in the zoogeographic comparisons. Twelve species appear to be endemic to the LRGV. Fifty-seven percent of the 227 species analyzed have the LRGV as either their northern or southern boundary. our representative collecting sites in the LRGV were chosen to make comparisons. The greatest diversity of weevil species of the LRGV occurs in the Sabal Palm Grove Sanctuary (32%). This may be due to more extensive collecting at this site. Approximately one-third of the total diversity of the LRGV occurs on these 32 acres of land. Plant associations are known for 33% of the weevils occurring in the LRGV, although some of the associations may have been recorded from areas outside of the LRGV. Out of the 433 plant associations, 41.3% involve the families Fabaceae, Malvaceae, and Asteraceae

The transcriptional response of Caenorhabditis elegans to ivermectin exposure identifies novel genes involved in the response to reduced food intake

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms

The Impact of Federal Regulation on Time to Equivalence and Compliance within the Orthopaedic Medical Device Industry

The Medical Device Amendments of 1976 (Public Law 94-295) consolidated and expanded existing federal authority over manufacturers of medical devices. This meant that any medical device manufactured after the Medical Device Amendment of 1976 needed to establish that it is substantially equivalent in terms of content, composition, intended use and related risk. This study was designed to investigate the influences on the process of notifying the Food and Drug Administration (FDA) of an orthopaedic medical device manufacturer\u27s intent to market a product. The study\u27s primary objectives were twofold: 1) determine the relationships of three independent variables (i.e., the company\u27s size and longevity) with the dependent variable, time to equivalence and 2) compare differences in mean days to equivalence based on specified company characteristics (i.e., regulatory affairs consultant use, regulatory training experiences, in-house regulatory department presence or absence, and attitudes toward influences on timely compliance). A survey instrument was returned by the regulatory manager at 39 companies representing 263 device equivalence submissions and 27 different medical device categories from 1977 through 1987. Four different statistical approaches were utilized: correlative-regressive, comparative, regressive-predictive, and distributive. From this research certain company characteristics which impact time to equivalence were identified. It was found that companies who have been manufacturing numerous years, manufacture more than one medical device, and use regulatory affairs professionals to assist with compliance issues, especially just following the enactment of a new regulation, may have predictably fewer days to equivalence than companies that do not possess these characteristics. Statistically significant relationships and differences in mean days to equivalence were computed for some variables

High glucose disrupts oligosaccharide recognition function via competitive inhibition : a potential mechanism for immune dysregulation in diabetes mellitus

Diabetic complications include infection and cardiovascular disease. Within the immune system, host-pathogen and regulatory host-host interactions operate through binding of oligosaccharides by C-type lectin. A number of C-type lectins recognise oligosaccharides rich in mannose and fucose – sugars with similar structures to glucose. This raises the possibility that high glucose conditions in diabetes affect protein-oligosaccharide interactions via competitive inhibition. Mannose binding lectin, soluble DC-SIGN & DC-SIGNR, and surfactant protein D, were tested for carbohydrate binding in the presence of glucose concentrations typical of diabetes, via surface plasmon resonance and affinity chromatography. Complement activation assays were performed in high glucose. DC-SIGN and DC-SIGNR expression in adipose tissues was examined via immunohistochemistry. High glucose inhibited C-type lectin binding to high-mannose glycoprotein and binding of DC-SIGN to fucosylated ligand (blood group B) was abrogated in high glucose. Complement activation via the lectin pathway was inhibited in high glucose and also in high trehalose - a nonreducing sugar with glucoside stereochemistry. DC-SIGN staining was seen on cells with DC morphology within omental and subcutaneous adipose tissues. We conclude that high glucose disrupts C-type lectin function, potentially illuminating new perspectives on susceptibility to infectious and inflammatory disease in diabetes. Mechanisms involve competitive inhibition of carbohydrate-binding within sets of defined proteins, in contrast to broadly indiscriminate, irreversible glycation of proteins