Computer Simulation of Adaptive Drug Infusion

Clinical drug infusion protocols, such as a single bolus followed by a constant drip, do not establish and maintain therapeutic drug levels in an optimal manner. We have investigated a system in which the patient, drug pump, drug assay, and a pump controller are incorporated into an adaptive configuration. The system, which we have simulated on a computer, uses an adaptive approach in which the pump controller operates with a model of the subject response. The model is fit to the specific subject by a regression analysis of the subject's response, obtained by assay of the subject's blood.     

Disinfection of wastewaters: high-energy electron vs gamma irradiation

A study was undertaken to examine the sensitivity of a wastewater population of coliphage, total coliforms and total flora present in raw sewage and secondary effluent after irradiating with similar doses delivered by a high-energy electron beam and y -radiation. The electron beam study was conducted on a large scale at the Virginia Key Wastewater Treatment Plant, Miami, Fla. The facility is equipped with a 1.5 MeV, 50 mA electron accelerator, with a wastewater flow rate of 8 ls⁻¹. Concurrent y-radiation studies were conducted at laboratory scale using a 5000 Ci, ⁶⁰Co y -source. Three logs reduction of all three test organisms were observed at an electron beam dose of 500 krads, while at least four logs reduction were observed at the same dose utilizing the y-source.     

Action of bleomycin on structural mimics of intermediates in DNA double-strand cleavage

Bleomycin-induced cleavage was examined in several nicked, gapped, or intact duplex DNA substrates, including a structure designed to mimic a proposed singly nicked intermediate in double-strand cleavage. This nicked structure appeared to correctly target the second cleavage event in the complementary strand, resulting in a blunt-ended double-strand break, similar to that induced directly by bleomycin alone in an intact duplex of the same sequence. A one-base-gapped structure was markedly less efficient in correctly targeting bleomycin attack in the complementary strand. The results are consistent with a model of bleomycin-induced double-strand cleavage in which the nick formed by the initial bleomycin attack serves to target secondary attack to a specific position in the complementary strand, resulting in a double-strand break with a defined geometry.     

Tributary use and large-scale movements of grass carp in Lake Erie

Infrequent captures of invasive, non-native grass carp (Ctenopharyngodon idella) have occurred in Lake Erie over the last 30+ years, with recent evidence suggesting wild reproduction in the lake’s western basin (WB) is occurring. Information on grass carp movements in the Laurentian Great Lakes is lacking, but an improved understanding of large-scale movements and potential areas of aggregation will help inform control strategies and risk assessment if grass carp spread to other parts of Lake Erie and other Great Lakes. Twenty-three grass carp captured in Lake Erie’s WB were implanted with acoustic transmitters and released. Movements were monitored with acoustic receivers deployed throughout Lake Erie and elsewhere in the Great Lakes. Grass carp dispersed up to 236 km, with approximately 25% of fish dispersing greater than 100 km from their release location. Mean daily movements ranged from <0.01 to 2.49 km/day, with the highest daily averages occurring in the spring and summer. The Sandusky, Detroit, and Maumee Rivers, and Plum Creek were the most heavily used WB tributaries. Seventeen percent of grass carp moved into Lake Erie’s central or eastern basins, although all fish eventually returned to the WB. One fish emigrated from Lake Erie through the Huron-Erie Corridor and into Lake Huron. Based on our results, past assessments may have underestimated the potential for grass carp to spread in the Great Lakes. We recommend focusing grass carp control efforts on Sandusky River and Plum Creek given their high use by tagged fish, and secondarily on Maumee and Detroit Rivers.     

Spatial ecology of common carp (Cyprinus carpio) in Lake Winnipeg and its potential for management actions

Common carp feeding and spawning behaviours negatively impact the functioning of marsh ecosystems. In the Netley-Libau Marsh, situated on the southern end of Lake Winnipeg, water level regulations, nonpoint source nutrient pollution, and the non-native common carp are thought to be the main contributors to the degradation of the marsh habitat. Using acoustic telemetry, we analysed the movement rate, frequency and timing of suspected spawning migrations, spatial ecology, and aggregation of common carp in the Lake Winnipeg drainage over a three year time period. Common carp moved the farthest during the open water period when water temperature was >5 °C. Their annual migration into Netley-Libau Marsh was correlated to ordinal date. Common carp left the marsh in late spring/early summer, presumably feeding in Lake Winnipeg, before moving to overwintering sites situated in Traverse Bay and Lake Winnipeg, where they arrived typically by October and formed aggregations. These findings will inform habitat and fisheries managers in the effort to undertake evidence-based management actions. The predictability of the movements and the tendency for common carp to aggregate indicates that exclusion techniques and commercial fishing may represent viable management solutions.     

A probabilistic fire-protection siting model with joint vehicle reliability requirements

A probabilistic fire-protection siting model is described that places capacitated stations, engine companies, and truck companies in such a way that the population or calls covered by an engineand a truck with a joint reliability of at least is maximized. Probabilistic constraints are developed and numerical equivalents are found for the probability requirement for proximate server presence. The multiple co-location of servers at stations and the use of stations with a limited capacity are also investigated. Structures are utilized that preserve the integer properties when the model is solved by linear programming relaxation.An earlier version of this paper was presented at the 37th North American Meetings, Boston, November 1990.     

The Neurovascular Unit Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.     

Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL^pro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL^pro. Moreover, we report the discovery of isoindolines as a new class of potent PL^pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL^pro are valuable starting points for the development of new pan-coronaviral inhibitors.     

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.