Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

An enhanced Tabu search Cell formation Algorithm for Cellular Manufacturing System

The major benefit of using Cellular manufacturing systems (CMS) is the improvement in efficiency and reduction in the production time. In a CMS the part families and machine parts are identified to minimise the inter and intracellular movement and maximise the utilisation of machines within each cell. Many scholars have proposed methods for the evaluation of machine cell part layouts with single routes; this paper introduces a modified Hybrid Tabu Search Algorithm (HTSA) referred to as Hybrid Algorithm in this study for machine cell part layouts having multiple routes as well. The primary objective of this paper is to minimise the inter and intracellular movement using a hybrid algorithm. The paper presents a comparative analysis of the existing and the proposed algorithms, proving that the proposed hybrid algorithm is simple, easy to understand, and has a remarkable efficiency with a runtime of 5.6 seconds.

An active inference model of hierarchical action understanding, learning and imitation

We advance a novel computational model of the acquisition of a hierarchical action repertoire and its use for observation, understanding and motor control. The model is grounded in a principled framework to understand brain and cognition: active inference. We exemplify the functioning of the model by presenting four simulations of a tennis learner who observes a teacher performing tennis shots and forms hierarchical representations of the observed actions - including both actions that are already in her repertoire and novel actions - and finally imitates them. Our simulations that show that the agent’s oculomotor activity implements an active information sampling strategy that permits inferring the kinematics aspects of the observed movement, which lie at the lowest level of the action hierarchy. In turn, this low-level kinematic inference supports higher-level inferences about deeper aspects of the observed actions, such as their proximal goals and intentions. Finally, the inferred action representations can steer imitative motor responses, but interfere with the execution of different actions. Taken together, our simulations show that the same hierarchical active inference model provides a unified account of action observation, understanding, learning and imitation. Finally, our model provides a computational rationale to explain the neurobiological underpinnings of visuomotor cognition, including the multiple routes for action understanding in the dorsal and ventral streams and mirror mechanisms.

Innate heuristics and fast learning support escape route selection in mice

When faced with imminent danger, animals must rapidly take defensive actions to reach safety. Mice can react to innately threatening stimuli in less than 250 milliseconds [1] and, in simple environments, use spatial memory to quickly escape to shelter [2,3]. Natural habitats, however, often offer multiple routes to safety which animals must rapidly identify and choose from to maximize the chances of survival [4]. This is challenging because while rodents can learn to navigate complex mazes to obtain rewards [5,6], learning the value of different routes through trial-and-error during escape from threat would likely be deadly. Here we have investigated how mice learn to choose between different escape routes to shelter. By using environments with paths to shelter of varying length and geometry we find that mice prefer options that minimize both path distance and path angle relative to the shelter. This choice strategy is already present during the first threat encounter and after only ~10 minutes of exploration in a novel environment, indicating that route selection does not require experience of escaping. Instead, an innate heuristic is used to assign threat survival value to alternative paths after rapidly learning the spatial environment. This route selection process is flexible and allows quick adaptation to arenas with dynamic geometries. Computational modelling of different classes of reinforcement learning agents shows that the observed behavior can be replicated by model-based agents acting in an environment where the shelter location is rewarding during exploration. These results show that mice combine fast spatial learning with innate heuristics to choose escape routes with the highest survival value. They further suggest that integrating priors acquired through evolution with knowledge learned from experience supports adaptation to changing environments while minimizing the need for trial-and-error when the errors are very costly.

Community Collaborations & Technology Successfully Connect Isolated Older Adults to Education & Activities

Providing programs, activities and education to older adults (OA) is a challenge under normal circumstances. The Arkansas Geriatric Education Collaborative (AGEC) is a HRSA Geriatric Workforce Enhancement Program with a mission to “provide high quality programs that support healthy aging in Arkansas.” Prior to the pandemic, AGEC educators provided face-to-face programs to OA’s through senior centers, places of worship and other public venues. The pandemic changed all that. In-person programs were replaced with zoom presentations, social media events and pre-recorded programs placed on websites and patient-learn platforms for 24/7 viewing. Gaining viewership proved difficult and after collaborative research, it was determined the major barrier was a digital divide between access, usage and knowledge of digital platforms. To overcome this barrier, AGEC utilized TV, radio, libraries, digital infographics, newsletters and video tips addressing Wi-Fi and technology training. Videos, distributed via multiple routes, addressed basic topics such as “Creating and Utilizing Zoom and Facebook accounts” and “how to improve telehealth visits”. After establishment of a regular audience, AGEC engaged new and established partners and hosted a plethora of educational programs and activities further expanding the viewing audiences. In addition, with personalized emails and targeted marketing, AGEC engaged OA audiences in caregiving workshops, on-line caregiver support groups, telephone check-ins and exercise programs. Many OAs have found ways to bridge the digital divide and are engaged and active with educational and program activities and have used their new skills to connect with other OAs, grandkids, friends and even their spiritual communities.

Fan-shaped Spectrums of Species and Paleopolyploidy for Foundation of Crossbreeding Evolution

Although Darwin‘s evolutionary mutation theory has been widely accepted, many endeavors tried to challenge it. With more and more observation of successful hybridization and hybrids, the sexual isolation between species has become vague. The mechanism of evolution has been expanded from the classical model of evolution to multiple routes of speciation. Furthermore, a fundamental crossbreeding theory has been raised and proved by two lines of evidences: paleopolyploidy and fan-shaped spectrum of species. Ancient genome duplications are widespread throughout eukaryotic lineages, particularly in plants. The genome polyploidization can break through the sexual incompatibility between diploid counterparts to hybridize and produce new species. By comparing characteristics, all species in every taxon, both in the extinct fossil and extant organisms, can be arranged into fan-shaped spectrum according to their similarity: left primitive type-middle advanced type-right primitive type. The species are primitive at the two ends and advanced at the middle. The primitive two species always resemble two types of more primitive species that can be confirmed as their ancestors respectively, and the middle species is half similar to the two ancestors respectively. These suggest that the species in the spectrum come from two different ancestors by crossbreeding and gene combination. As a sum, advanced species originated from crossbreeding of two primitive ancestors, by major method of polyploidization, and proved by results of fan-shaped spectrum of species. Then, sex is the cause, force and opportunity for evolution.

Energy-Efficient and Disjoint Multipath Using Face routing in Wireless Sensor Networks

In WSNs, multipath is well-known as a method to improve the reliability of packet delivery by making multiple routes from a source node to a destination node. To improve reliability and load-balancing, it is important to ensure that disjoint characteristics of multipath do not use same nodes during path generation. However, when multipath studies encounter a hole area from which is hard to transmit data packets, they have a problem with breaking the disjoint features of multipath. Although existing studies propose various strategies to bypass hole areas, they have side effects that significantly accelerate energy consumption and packet transmission delay. Therefore, to retain the disjoint feature of multipath, we propose a new scheme that can reduce delay and energy consumption for a node near a hole area using two approaches—global joint avoidance and local avoidance. This scheme uses global joint avoidance to generate a new path centered on a hole area and effectively bypasses the hole area. This scheme also uses local joint avoidance that does not select the same nodes during new path generation using a marking process. In simulations, the proposed scheme has an average 30% improvement in terms of average energy consumption and delay time compared to other studies.

Neuropharmacology

Medications used in the treatment of nervous system disorders typically modulate neurotransmitter function or action potential propagation and alter neurologic function. This chapter reviews the principles of pharmacokinetics, the major targets for drug action to provide a basis for understanding how medications exert their action, and disease-specific treatments. An understanding of the pharmacokinetic principles of neurologic medications is important for prescribing and ordering medication. Multiple routes of administration, including intravenous, sublingual, intramuscular, subcutaneous, rectal, oral, and transdermal, are available for delivery of neurologic medications.

Emergence of Parafilaria bovicola in Austria

Veterinarians reported cases of cutaneous bleeding in cattle in Austria in the spring and summer of 2020. It was our goal to confirm the tentative diagnosis of parafilariosis by identifying Parafilaria bovicola in exudate samples using molecular methods for the first time in Austria. We asked veterinarians in the field to collect exudate from typical lesions on cattle. We performed polymerase chain reactions (PCRs) and sequenced a 674-bp section of the mitochondrial cytochrome oxidase subunit I in all positive samples. Overall, in 57 of 86 samples, P. bovicola was confirmed by PCR in cattle from Lower Austria, Upper Austria, Styria, Salzburg, Carinthia, and Tyrol. Sequencing detected four different haplotypes or genotypes, respectively, indicating multiple routes of introduction. We conclude that parafilariosis has spread in Austria and we expect that the number of reports of clinical signs and losses due to carcass damage will increase in the future.

A Multipath Cluster-Based Routing Protocol For Mobile Ad Hoc Networks

A MANET (Mobile Ad-hoc Network) is a group of mobile network nodes dynamically forming a network without any pre-existing infrastructure. Multi-path routing protocols in MANETs try to discover and use multiple routes between source and destination nodes. Multipath routing is typically used to reduce average delay, increase transmission reliability, provide load balancing among multiple routes, and improve security and overall QoS (Quality of Service). In this paper, the Cluster-Based Routing Protocol (CBRP), which is a single path MANET protocol is enhanced to use multiple paths. The traffic will be distributed among multiple paths to reduce network traffic congestion and decrease delay. An analytical model is used for multipath and single path CBRP routing protocols in MANETs to estimate the end-to-end delay and queue length. The analytical results show that the average delay and average queue length in multipath CBRP are less than the average delay and queue length in single path CBRP.