Search

Genetically modified mice are engineered as models for human diseases. These mouse models include inbred strains, mutants, gene knockouts, gene knockins, and ‘humanized’ mice. Each mouse model is engineered to mimic a specific disease based on a theory of the genetic basis of that disease. For example, to test the amyloid theory of Alzheimer’s disease, mice with amyloid precursor protein genes are engineered, and to test the tau theory, mice with tau genes are engineered. This paper discusses the importance of mouse models in basic research, drug discovery, and translational research, and examines the question of how to define the “best” mouse model of a disease. The critiques of animal models and the caveats in translating the results from animal models to the treatment of human disease are discussed. Since many diseases are heritable, multigenic, age-related and experience-dependent, resulting from multiple gene-gene and gene-environment interactions, it will be essential to develop mouse models that reflect these genetic, epigenetic and environmental factors from a developmental perspective. Such models would provide further insight into disease emergence, progression and the ability to model two-hit and multi-hit theories of disease. The summary examines the biotechnology for creating genetically modified mice which reflect these factors and how they might be used to discover new treatments for complex human diseases such as cancers, neurodevelopmental and neurodegenerative diseases.

Alzheimer's disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg-AD) mouse model of Alzheimer's Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17-month-old female 3xTg-AD mice and their B6129S/F2 wildtype controls. Mice were filmed using a high-speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3-month-old 3xTg-AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre-contact mean angular position at 3 months and whisking amplitude at 17 months of age differed between the 3xTg-AD and wildtype mice. During object contact 3xTg-AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg-AD mouse model.

Although Alzheimer’s disease is most often studied in terms of memory impairments, olfactory dysfunction begins in the early stages. We tested olfactory learning, sensitivity, and response bias using signal detection methods in 12-month-old male and female 5xFAD mice and their wildtype controls in the operant olfactometer. Odor detection was not reduced in the 5xFAD mice, but learning was, which was worse in female 5xFAD mice than in males. Female mice were more conservative in their response strategy. Signal detection analysis allows us to discriminate between cognitive and sensory deficits of male and female mouse models of AD.

The 5xFAD mouse model of Alzheimer's disease (AD) develops age-related neuropathology and sensory, motor, and cognitive impairments. The purpose of this study was to examine whether age-related changes in motor function affected working memory performance in 5xFAD mice in the Hebb-Williams Maze (HWM). At 6 months of age, the 5xFAD mice performed better than the WT (B6SJL) mice on the accelerating rotarod, but much worse at 12 months of age. The 5xFAD and WT mice did not differ in days to acquisition in the HWM at 6 months of age, but the WT mice took longer at 12 months of age. The number of errors increased with maze difficulty and at 6 months of age, the 5xFAD mice made more errors than the WT mice only on difficult problems. At 12 months of age 5xFAD mice made more errors than WT mice at each level of problem difficulty. The latency to solve the problems was higher for the 5xFAD mice than the WT mice in the difficult problems at 6 months of age and in the intermediate problems at 12 months of age. Although body weight had some effect on rotarod performance, there were no systematic effects of motor deficits on either errors or latency measures in the test trials of the HWM. These results indicate that the 5xFAD mice had deficits in working memory in the HWM and that these deficits were not confounded by impaired motor performance.

Since the work of Semon was rediscovered by Schacter in 1978, there has been a renewed interest is searching for the “engram” as the locus of memory in the brain and Hebb’s cell assembly has been equated with Semon’s engram. There have been many theories of memory involving some concept of synaptic change, culminating in the “Hebb Synapse” theory in 1949. However, Hebb said that the idea that any two cells or systems of cells that are repeatedly active at the same time will tend to become “associated,” was not his idea, but an old one. In this manuscript we give an overview of some of the theories of the neural basis of learning and memory before Hebb and describe the synaptic theory of William McDougall, which appears to have been an idea ahead of its time; so far ahead of its time that it was completely ignored by his contemporaries. We conclude by examining some critiques of McDougall’s theory of inhibition and with a short discussion on the fate of neuroscientists whose ideas were neglected when first presented but were accepted as important many decades later.

Pathologic inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice in early and late stages of disease progression, and characterized tissue-specific epigenetic regulation of Txnip gene expression. We show that cognitive deficits in 7-month–old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in amyloid β 40 (Aβ40)/Aβ42 and tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory cytokine production in 17-month–old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor [Aβ42 or CCCTC-binding factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline; and they provide a potential mechanism for Txnip gene regulation in normal and pathologic conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aβ40/Aβ42 targeted AD therapies.

We investigated interval timing behavior of 10-month-old male and female 3xTg-AD mice compared with their B6129F2/J wild type controls using the peak interval procedure with a 15 s target interval. Multiple parameters reflecting different aspects of timing performance were extracted from steady-state anticipatory nose-poking behavior using two different approaches: single trial analyses and average response curve analyses. These measures can dissociate the differences in performance due to distortions in the interval timing ability or to motivational decline (i.e. apathy); both of which have been reported in Alzheimer patients. We found that the interval timing ability of male and female 3xTg-AD mice did not differ from wild-type controls. However, in measures reflecting motivational state, we found significant sex differences regardless of genotype. Specifically, female mice initiated anticipatory responding later in the trial and had lower response amplitudes than males. Although our findings can also be interpreted in terms of differences in temporal control for response initiation, they more strongly suggest the effect of differential incentive motivation between sexes on timing behavior in these mice.

Today’s selection of DC buildings features a diverse set of electrical topologies and turnkey solutions, and each has specific design trade-offs and optimizations. Designers desperately need standardized metrics and procedures for measurement and verification (M&V) to analyze and compare the advantages of each DC solution to traditional AC building networks. This work develops the Measurement-Informed Modeling (MIM) method, which can be used to determine full-building efficiency and energy savings. The MIM M&V procedure develops a building model, and refines the model with metered data. This work demonstrates the MIM method by measuring the full-building efficiency of two DC buildings operated by the Institute of Building Research in Shenzhen, China. The MIM procedure can ultimately be used to compare and improve the efficiency of various DC topologies.

Since the work of Semon was rediscovered by Schacter in 1978, there has been a renewed interest is searching for the “engram” as the locus of memory in the brain and Hebb’s cell assembly has been equated with Semon’s engram. There have been many theories of memory involving some concept of synaptic change, culminating in the “Hebb Synapse” theory in 1949. However, Hebb said that the idea that any two cells or systems of cells that are repeatedly active at the same time will tend to become “associated,” was not his idea, but an old one. In this manuscript we give an overview of some of the theories of the neural basis of learning and memory before Hebb and describe the synaptic theory of William McDougall, which appears to have been an idea ahead of its time; so far ahead of its time that it was completely ignored by his contemporaries. We conclude by examining some critiques of McDougall’s theory of inhibition and with a short discussion on the fate of neuroscientists whose ideas were neglected when first presented but were accepted as important many decades later.

DC microgrids have become a prevalent topic in research in part due to the expected superior efficiency of DC/DC converters compared to their AC/DC counterparts. Although numerous side-by-side analyses have quantified the efficiency benefits of DC power distribution, these studies all modeled converter loss based on product data that varied in component quality and operating voltage. To establish a fair efficiency comparison, this work derives a formulaic loss model of a DC/DC and an AC/DC PFC boost converter. These converters are modeled with identical components and an equivalent input and output voltage. Simulated designs with real components show AC/DC boost converters between 100 W to 500 W having up to 2.5 times more loss than DC/DC boost converters. Although boost converters represent a fraction of electronics in buildings, these loss models can eventually work toward establishing a comprehensive model-based full-building analysis.

Neurological disorders comprise 20% of hospital admissions in Cameroon. The burden of neurological disorders is increasing, especially in children and the elderly. However, there are very few neurologists, psychiatrists, gerontologists and neuropsychologists trained in the treatment of neurological disorders in Cameroon and there are very few facilities for training in basic and clinical neuroscience. Although non-governmental organizations such as the International Brain Research Organization (IBRO), International Society of Neurochemistry (ISN), and Teaching and Research in Natural Sciences for Development (TReND) in Africa have stepped in to provide short training courses and workshops in neuroscience, these are neither sufficient to train African neuroscientists nor to build the capacity to train neuroscience researchers and clinicians. There has also been little support from universities and the government for such training. While some participants of these schools have managed to form collaborations with foreign researchers and have been invited to study abroad, this does not facilitate the training of neuroscientists in Cameroon. Moreover, the research infrastructure for training in neuroscience remains limited. This is reflected in the low research output from Cameroonian universities in the field. In this review, we describe the burden of neurological disorders in Cameroon and outline the outstanding efforts of local scientists to develop the discipline of neuroscience, which is still an emerging field in Cameroon. We identify key actionable steps towards the improvement of the scientific capacity in neuroscience in Cameroon: (1) develop targeted neuroscience training programs in all major universities in Cameroon; (2) implement a thriving scientific environment supported by international collaborations; (3) focus on the leadership and the mentorship of both local and senior neuroscientists; (4) develop public awareness and information of policy makers to increase governmental funding for neuroscience research., Highlights • Improving scientific capacity to tackle the neurological diseases burden in Cameroon is urgent. • Neuroscience schools and advocated researchers shape the future of neuroscience in Cameroon. • Public-private partnerships are required for sustainable country impact of neuroscience schools.

The membrane-associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock-out mice (MDGA2+/- ) are models of ASD. We examined the behavioral phenotypes of male and female MDGA2+/- and wildtype mice on C57BL6/NJ and C57BL6/N backgrounds at 2 months of age and measured MDGA2, neuroligin 1 and neuroligin 2 levels at 7 months. Mice on the C57BL6/NJ background performed better than those on the C57BL6/N background in visual ability and in learning and memory performance in the Morris water maze and differed in measures of motor behavior and anxiety. Mice with the MDGA2+/- genotype differed from WT mice in motor, social and repetitive behavior and anxiety, but most of these effects involved interactions between MDGA2+/- genotype and background strain. The background strain also influenced MDGA2 levels and NLGN2 association in MDGA2+/- mice. Our findings emphasize the importance of the background strain used in studies of genetically modified mice.

The membrane-associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock-out mice (MDGA2

With the falling costs of solar arrays and battery storage and reduced reliability of the grid due to natural disasters, small-scale local generation and storage resources are beginning to proliferate. However, very few software options exist for integrated control of building loads, batteries and other distributed energy resources. The available software solutions on the market can force customers to adopt one particular ecosystem of products, thus limiting consumer choice, and are often incapable of operating independently of the grid during blackouts. In this paper, we present the &ldquo, Solar+ Optimizer&rdquo, (SPO), a control platform that provides demand flexibility, resiliency and reduced utility bills, built using open-source software. SPO employs Model Predictive Control (MPC) to produce real time optimal control strategies for the building loads and the distributed energy resources on site. SPO is designed to be vendor-agnostic, protocol-independent and resilient to loss of wide-area network connectivity. The software was evaluated in a real convenience store in northern California with on-site solar generation, battery storage and control of HVAC and commercial refrigeration loads. Preliminary tests showed price responsiveness of the building and cost savings of more than 10% in energy costs alone.

Today's selection of DC microgrid buildings features a diverse set of electrical topologies and turnkey solutions, each with specific design trade-offs and optimizations. Designers desperately need standardized metrics and procedures for measurement and verification (M&V) to analyze and compare the advantages of each DC solution to traditional AC building networks. This work develops M&V procedures for quantifying and comparing the energy efficiency and power quality in buildings. To calculate full-building efficiency, this work introduces the measurement-informed modeling method, a procedure that develops and refines a building's energy model with metered data. To quantify power quality, this work defines a new voltage quality index that applies to both AC and DC buildings. This article describes the equipment, instrumentation, and operation necessary to calculate the efficiency and power quality. It then demonstrates these methods with a set of field tests. These M&V procedures can ultimately be used to compare and improve the efficiency and power quality of various DC topologies.

The buildings are conventionally operated to maintain homogeneous indoor ambient conditions to maintain comfortable thermal and visual environments. However, maintaining these homogeneous condition...

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been reported to prevent neurodegenerative diseases such as Alzheimer's disease (AD) in both experimental and clinical/epidemiological studies. However, whether DHA and EPA from natural products exert similar or different neuroprotective effects and how these n-3 PUFAs target cellular and molecular mechanisms associated with neurodegenerative disease pathogenesis are unknown. In the present study, we used amyloid-β (Aβ)25-35-treated differentiated SH-SY5Y cells as a model of AD to compare the neuroprotective effect of DHA, EPA and their combination at various ratios. Administration of 20μM Aβ25-35 significantly decreased SH-SY5Y cell viability, the expression of nerve growth factor (NGF), its TrkA receptor, and the level of glutathione (GSH) and increased reactive oxygen species (ROS), nitric oxide, tumor necrosis factor (TNF)-α, brain derived neurotrophic factor (BDNF) and its TrkB receptor. Aβ25-35 also increased the Bax/Bcl-2 ratio and the expression of Caspase-3 in these cells. Compared with the Aβ group, pretreatment with DHA/EPA significantly reduced cell death, especially at ratio of 1:1 and 2:1 DHA/EPA or pure DHA. However, the most efficient ratio for reducing changes in ROS and GSH and for decreasing TNF-α appeared at ratio of 1:2 and 1:1, respectively. The ratio of 1:1, 2:1 and pure DHA resulted in significant increase in the level of NGF. Furthermore, pure DHA was the most efficient for reducing Bax/Bcl ratio and Caspase-3 expression. In conclusion, DHA, EPA and their combination differently modulated Aβ25-35-induced neurotoxicity in SH-SY5Y cells by exerting anti-oxidative, anti-inflammatory and neurotrophic effects.

The development of cheaper, more efficient access to space is fundamental to the viability of many current and future ambitions for space exploitation and exploration. Vehicle concepts that combine...

The APPswe/PS1dE9 mouse (line 85) is a double transgenic model of Alzheimer's disease (AD) with familial amyloid precursor protein and presenilin-1 mutations. These mice develop age-related behavioral changes reflective of the neuropsychiatric symptoms (altered anxiety-like behaviour, hyperactivity) and cognitive dysfunction (impaired learning and memory) observed in AD. The APPswe/PS1dE9 mouse has been used to examine the efficacy of therapeutic interventions on behaviour, despite previous difficulties in replicating behavioural phenotypes. Therefore, the purpose of this study was to establish the reliability of these phenotypes by further characterizing the behaviour of male APPswe/PS1dE9 and wild-type mice between 7 and 14 months of age. Mice were tested on the open-field over 5-days to examine emotionality, locomotor activity and inter-session habituation. Mice were also tested on the repeated-reversal water maze task and spontaneous alternation on the Y-maze to assess working memory. Sensori-motor gating was examined with acoustic startle and pre-pulse inhibition. Lastly contextual and cued (trace) memory was assessed with fear conditioning. The results show that among non-cognitive behaviours, APPswe/PS1dE9 mice have normal locomotor activity, anxiety-like behavior, habituation and sensori-motor gating. However, APPswe/PS1dE9 mice show impaired working memory on the repeated-reversal water-maze and impaired memory in contextual but not trace-cued fear conditioning. These results indicate that the APPswe/PS1dE9 (line 85) mice have deficits in some types of hippocampal-dependent learning and memory and, at the ages tested, APPswe/PS1dE9 mice model cognitive dysfunction but not neuropsychiatric symptoms.

Behind-the-meter distributed energy resources (DERs), including building solar photovoltaic (PV) technology and electric battery storage, are increasingly being considered as solutions to support carbon reduction goals and increase grid reliability and resiliency. However, dynamic control of these resources in concert with traditional building loads, to effect efficiency and demand flexibility, is not yet commonplace in commercial control products. Traditional rule-based control algorithms do not offer integrated closed-loop control to optimize across systems, and most often, PV and battery systems are operated for energy arbitrage and demand charge management, and not for the provision of grid services. More advanced control approaches, such as MPC control have not been widely adopted in industry because they require significant expertise to develop and deploy. Recent advances in deep reinforcement learning (DRL) offer a promising option to optimize the operation of DER systems and building loads with reduced setup effort. However, there are limited studies that evaluate the efficacy of these methods to control multiple building subsystems simultaneously. Additionally, most of the research has been conducted in simulated environments as opposed to real buildings. This paper proposes a DRL approach that uses a deep deterministic policy gradient algorithm for integrated control of HVAC and electric battery storage systems in the presence of on-site PV generation. The DRL algorithm, trained on synthetic data, was deployed in a physical test building and evaluated against a baseline that uses the current best-in-class rule-based control strategies. Performance in delivering energy efficiency, load shift, and load shed was tested using price-based signals. The results showed that the DRL-based controller can produce cost savings of up to 39.6% as compared to the baseline controller, while maintaining similar thermal comfort in the building. The project team has also integrated the simulation components developed during this work as an OpenAIGym environment and made it publicly available so that prospective DRL researchers can leverage this environment to evaluate alternate DRL algorithms.

Motor problems occur early in some patients with Alzheimer's disease (AD) and as the disease progresses many patients develop motor dysfunction. Motor dysfunction has been reported in some mouse models of AD, including the 5xFAD mouse, thus this model may be particularly useful for studying motor dysfunction in AD. In order to determine the extent of motor dysfunction in these mice, we tested 11-13 month old female 5xFAD and wildtype (WT) control mice in a battery of motor behaviour tasks. The 5xFAD mice showed hind limb clasping, weighed less and had slower righting reflexes than WT mice. In the open field, the 5xFAD mice travelled a shorter distance than the WT mice, spent less time moving and had a slower movement speed. The 5xFAD mice fell faster than the WT mice from the balance beam, wire suspension, grid suspension and rotarod tasks, indicating dysfunctions in balance, grip strength, motor co-ordination and motor learning. The 5xFAD mice had a short, shuffling gait with a shorter stride length than WT mice and had a slower swim speed. The 5xFAD mice also failed to show an acoustic startle response, likely due to motor dysfunction and previously reported hearing impairment. The 5xFAD mice did not show deficits in the ability of peripheral motor nerves to drive muscle output, suggesting that motor impairments are not due to dysfunction in peripheral motor nerves. These results indicate that the aged 5xFAD mice are deficient in numerous motor behaviours, and suggest that these mice may prove to be a good model for studying the mechanisms of motor dysfunction in AD, and motor behaviour might prove useful for assessing the efficacy of AD therapeutics. Motor dysfunction in 5xFAD mice must also be considered in behavioural tests of sensory and cognitive function so that performance is not confounded by impaired locomotor or swimming behaviour.

Hearing dysfunction has been associated with Alzheimer's disease (AD) in humans, but there is little data on the auditory function of mouse models of AD. Furthermore, characterization of hearing ability in mouse models is needed to ensure that tests of cognition that use auditory stimuli are not confounded by hearing dysfunction. Therefore, we assessed acoustic startle response and pre-pulse inhibition in the double transgenic 5xFAD mouse model of AD from 3-4 to 16 months of age. The 5xFAD mice showed an age-related decline in acoustic startle as early as 3-4 months of age. We subsequently tested auditory brainstem response (ABR) thresholds at 4 and 13-14 months of age using tone bursts at frequencies of 2-32 kHz. The 5xFAD mice showed increased ABR thresholds for tone bursts between 8 and 32 kHz at 13-14 months of age. Finally, cochleae were extracted and basilar membranes were dissected to count hair cell loss across the cochlea. The 5xFAD mice showed significantly greater loss of both inner and outer hair cells at the apical and basal ends of the basilar membrane than wild-type mice at 15-16 months of age. These results indicate that the 5xFAD mouse model of AD shows age-related decreases in acoustic startle responses, which are at least partially due to age-related peripheral hearing loss. Therefore, we caution against the use of cognitive tests that rely on audition in 5xFAD mice over 3-4 months of age, without first confirming that performance is not confounded by hearing dysfunction.

Historical distribution system reliability optimization approaches have relied on the creation of detailed feeder reliability models, which is extremely labor-intensive. This paper presents a reliability optimization approach using synthetic feeders that does not require creating a topologically-precise model, but can still perform an overall system assessment considering a wide range of reliability improvement options for far less modeling effort. The synthetic feeder approach is then applied to Hawaiian Electric&rsquo, s Oʻahu distribution system, to identify (1) the lowest cost required to achieve various levels of reliability improvement, and (2) an approximate reliability project portfolio for each level of spending.

Despite the recent interest in direct current (DC) power distribution in buildings, the market for DC-ready loads remains small. The existing DC loads in various products or research test beds are not always designed to efficiently leverage the benefits of DC. This work addresses a pressing need for a study into the development of efficient DC loads. In particular, it focuses on documenting and demonstrating how to best leverage a DC input to eliminate or improve conversion stages in a load’s power converter. This work identifies how typical building loads can benefit from DC input, including bath fans, refrigerators, wall adapters, task lights, and zone lighting. It then details the development of several prototypes that demonstrate efficiency savings with DC. The most efficient direct-DC loads are explicitly designed for DC from the ground up, rather than from an AC modification.