Heterosynaptic plasticity in biomembrane memristors controlled by pH.

Abstract: In biology, heterosynaptic plasticity maintains homeostasis in synaptic inputs during associative learning and memory, and initiates long-term changes in synaptic strengths that nonspecifically modulate different synapse types. In bioinspired neuromorphic circuits, heterosynaptic plasticity may be used to extend the functionality of two-terminal, biomimetic memristors. In this article, we explore how changes in the pH of droplet interface bilayer aqueous solutions modulate the memristive responses of a lipid bilayer membrane in the pH range 4.97-7.40. Surprisingly, we did not find conclusive evidence for pH-dependent shifts in the voltage thresholds (V*) needed for alamethicin ion channel formation in the membrane. However, we did observe a clear modulation in the dynamics of pore formation with pH in time-dependent, pulsed voltage experiments. Moreover, at the same voltage, lowering the pH resulted in higher steady-state currents because of increased numbers of conductive peptide ion channels in the membrane. This was due to increased partitioning of alamethicin monomers into the membrane at pH 4.97, which is below the pKa (~5.3-5.7) of carboxylate groups on the glutamate residues of the peptide, making the monomers more hydrophobic. Neutralization of the negative charges on these residues, under acidic conditions, increased the concentration of peptide monomers in the membrane, shifting the equilibrium concentrations of peptide aggregate assemblies in the membrane to favor greater numbers of larger, increasingly more conductive pores. It also increased the relaxation time constants for pore formation and decay, and enhanced short-term facilitation and depression of the switching characteristics of the device. Modulating these thresholds globally and independently of alamethicin concentration and applied voltage will enable the assembly of neuromorphic computational circuitry with enhanced functionality. Impact statement: We describe how to use pH as a modulatory "interneuron" that changes the voltage-dependent memristance of alamethicin ion channels in lipid bilayers by changing the structure and dynamical properties of the bilayer. Having the ability to independently control the threshold levels for pore conduction from voltage or ion channel concentration enables additional levels of programmability in a neuromorphic system. In this article, we note that barriers to conduction from membrane-bound ion channels can be lowered by reducing solution pH, resulting in higher currents, and enhanced short-term learning behavior in the form of paired-pulse facilitation. Tuning threshold values with environmental variables, such as pH, provide additional training and learning algorithms that can be used to elicit complex functionality within spiking neural networks. Supplementary information: The online version contains supplementary material available at 10.1557/s43577-022-00344-z.

Ankle Bracing Alters Coordination and Coordination Variability in Individuals With and Without Chronic Ankle Instability.

CONTEXT: Ankle bracing is an effective form of injury prophylaxis implemented for individuals with and without chronic ankle instability, yet mechanisms surrounding bracing efficacy remain in question. Ankle bracing has been shown to invoke biomechanical and neuromotor alterations that could influence lower-extremity coordination strategies during locomotion and contribute to bracing efficacy. OBJECTIVE: The purpose of this study was to investigate the effects of ankle bracing on lower-extremity coordination and coordination dynamics during walking in healthy individuals, ankle sprain copers, and individuals with chronic ankle instability. DESIGN: Mixed factorial design. SETTING: Laboratory setting. PARTICIPANTS: Forty-eight recreationally active individuals (16 per group) participated in this cross-sectional study. INTERVENTION: Participants completed 15 trials of over ground walking with and without an ankle brace. MAIN OUTCOME MEASURES: Coordination and coordination variability of the foot-shank, shank-thigh, and foot-thigh were assessed during stance and swing phases of the gait cycle through analysis of segment relative phase and relative phase deviation, respectively. RESULTS: Bracing elicited more synchronous, or locked, motion of the sagittal plane foot-shank coupling throughout swing phase and early stance phase, and more asynchronous motion of remaining foot-shank and foot-thigh couplings during early swing phase. Bracing also diminished coordination variability of foot-shank, foot-thigh, and shank-thigh couplings during swing phase of the gait cycle, indicating greater pattern stability. No group differences were observed. CONCLUSIONS: Greater stability of lower-extremity coordination patterns as well as spatiotemporal locking of the foot-shank coupling during terminal swing may work to guard against malalignment at foot contact and contribute to the efficacy of ankle bracing. Ankle bracing may also act antagonistically to interventions fostering functional variability.

Towards harmonized standards for freshwater biodiversity monitoring and biological assessment using benthic macroinvertebrates.

Monitoring programs at sub-national and national scales lack coordination, harmonization, and systematic review and analysis at continental and global scales, and thus fail to adequately assess and evaluate drivers of biodiversity and ecosystem degradation and loss at large spatial scales. Here we review the state of the art, gaps and challenges in the freshwater assessment programs for both the biological condition (bioassessment) and biodiversity monitoring of freshwater ecosystems using the benthic macroinvertebrate community. To assess the existence of nationally- and regionally- (sub-nationally-) accepted freshwater benthic macroinvertebrate protocols that are put in practice/used in each country, we conducted a survey from November 2022 to May 2023. Responses from 110 respondents based in 67 countries were received. Although the responses varied in their consistency, the responses clearly demonstrated a lack of biodiversity monitoring being done at both national and sub-national levels for lakes, rivers and artificial waterbodies. Programs for bioassessment were more widespread, and in some cases even harmonized among several countries. We identified 20 gaps and challenges, which we classed into five major categories, these being (a) field sampling, (b) sample processing and identification, (c) metrics and indices, (d) assessment, and (e) other gaps and challenges. Above all, we identify the lack of harmonization as one of the most important gaps, hindering efficient collaboration and communication. We identify the IUCN SSC Global Freshwater Macroinvertebrate Sampling Protocols Task Force (GLOSAM) as a means to address the lack of globally-harmonized biodiversity monitoring and biological assessment protocols.

Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1.

The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.

Making the most of existing research: an evidence gap map of the effects of food systems interventions in low-income and middle-income countries.

OBJECTIVE: Identify and describe the available evidence on the effects food systems interventions on food security and nutrition outcomes in low-income and middle-income countries. METHODS: An adapted version of the high-level panel of experts food systems framework defined the interventions and outcomes included studies. Included study designs were experimental and quasi-experimental quantitative impact evaluations and systematic reviews. Following standards for evidence gap maps developed by 3ie, a systematic search of 17 academic databases and 31 sector-specific repositories in May 2020 identified articles for inclusion. Trained consultants screened titles/abstracts, then full texts of identified articles. Studies meeting eligibility criteria had meta-data systematically extracted and were descriptively analysed. Systematic reviews were critically appraised. RESULTS: The map includes 1838 impact evaluations and 178 systematic reviews. The most common interventions, with over 100 impact evaluations and 20 systematic reviews each, were: provision of supplements, fortification, nutrition classes, direct provision of foods and peer support/counselling. Few studies addressed national-level interventions or women's empowerment. The most common final outcomes were: anthropometry, micronutrient status, and diet quality and adequacy. Intermediate outcomes were less studied.Most evaluations were conducted in sub-Saharan Africa (33%) or South Asia (20%). Many studies occurred in lower-middle-income countries (43%); few (7%) were in fragile countries. Among studies in a specific age group, infants were most frequently included (19%); 14% of these also considered mothers.Few evaluations considered qualitative or cost analysis; 75% used randomisation as the main identification strategy. DISCUSSION: The uneven distribution of research means that some interventions have established impacts while other interventions, often affecting large populations, are underevaluated. Areas for future research include the evaluation of national level policies, evaluation of efforts to support women's empowerment within the food system, and the synthesis of dietary quality. Quasi-experimental approaches should be adopted to evaluate difficult to randomise interventions.

The role of hydro-environmental factors in Mayfly (Ephemeroptera, Insecta) community structure: Identifying threshold responses.

Freshwater organisms are threatened by changes in stream flow and water temperature regimes due to global climate change and anthropogenic activities. Threats include the disappearance of narrow-tolerance species and loss of favorable thermal conditions for cold-adapted organisms. Mayflies are an abundant and diverse indicator of river health that performs important functional roles. The relative importance of key hydro-environmental factors such as water temperature and flow volumes in structuring these communities has rarely been explored in the tropical regions of Africa. Here, we investigate the response of mayfly species diversity to these factors in the Luvuvhu catchment, a strategic water source area in the arid northeastern region of South Africa. Mayfly larvae were sampled monthly in stones-in-current biotopes across 23 sites over a one-year period. The relationship between these environmental drivers and mayfly diversity was modeled using linear mixed effects models (LMMs) and a model-based multivariate approach. Threshold Indicator Taxa Analysis (TITAN) was used to model the response of mayfly species to important gradients and identify thresholds of change. Site-specific characteristic were the most important predictor of mayfly diversity, and there was considerable variation over time, with mayfly diversity peaking during winter. Along this, gradient temperature was the best predictor of assemblage structure, with five out of six reliable indicator species being cold-adapted, and a community threshold response at 19°C. Results support laboratory-based thresholds of temperature for mayfly species survival and development, extending empirical evidence to include field-based observations. Increased global (climate change) and local (riparian vegetation removal, impoundments) changes are predicted to have negative impacts on mayfly diversity and ultimately on ecosystem function.

The functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods.

BACKGROUND: Evaluation of the effects of candidate drugs on the nervous system in preclinical safety pharmacology studies utilises a global neurobehavioral assessment, usually in the rat. This either takes the form of the functional observational battery (FOB) or modified Irwin Test, both of which evaluate effects across 4 functional domains: autonomic, neuromuscular, sensorimotor and behavioral. Although there is a great deal of overlap in the parameters they address, the two tests approach the assessments slightly differently. We undertook a broad pharmacological validation of both the FOB and the Irwin test, and compared the two outcomes. METHODS: Male rats (6 per treatment group) were used to assess each of 12 reference drugs alongside vehicle controls in separate FOB and Irwin studies. The drugs compared in the two study types were chlorpromazine, chlordiazepoxide, clonidine, baclofen, (+)-amphetamine, harmaline, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, physostigmine, picrotoxin, yohimbine and atropine. There is a high degree of semantic equivalence in the parameters assessed in the autonomic domain between the two tests, with a lower degree of equivalence for neuromuscular and behavioral domains, whereas sensorimotor reflex testing in the FOB is far more extensive than in the Irwin test. RESULTS: Across the set of reference drugs, concordance between the two tests was generally good across the 4 functional domains at the 'domain' level (i.e., detecting 'an effect'), whereas there was generally a poor concordance at the individual parameter level. However, this was partially explained by variability between repeated studies on a single reference drug using the same test (FOB or Irwin). CONCLUSIONS: Both tests are 'fit-for-purpose' in detecting effects of candidate drugs on the nervous system. We would encourage the global safety pharmacology community to consider whether (a) the tests could be combined into one industry standard; (b) candidate drugs could be triaged according to CNS penetration, with the level of scrutiny in the CNS core battery assessment adjusted accordingly and (c) whether new home cage technology could be applied to semi-automate the preclinical neurobehavioral assessment.

Trophic overlap between fish and riparian spiders: potential impacts of an invasive fish on terrestrial consumers.

Studies on resource sharing and partitioning generally consider species that occur in the same habitat. However, subsidies between linked habitats, such as streams and riparian zones, create potential for competition between populations which never directly interact. Evidence suggests that the abundance of riparian consumers declines after fish invasion and a subsequent increase in resource sharing of emerging insects. However, diet overlap has not been investigated. Here, we examine the trophic niche of native fish, invasive fish, and native spiders in South Africa using stable isotope analysis. We compared spider abundance and diet at upstream fishless and downstream fish sites and quantified niche overlap with invasive and native fish. Spider abundance was consistently higher at upstream fishless sites compared with paired downstream fish sites, suggesting that the fish reduced aquatic resource availability to riparian consumers. Spiders incorporated more aquatic than terrestrial insects in their diet, with aquatic insects accounting for 45-90% of spider mass. In three of four invaded trout rivers, we found that the average proportion of aquatic resources in web-building spider diet was higher at fishless sites compared to fish sites. The probability of web-building and ground spiders overlapping into the trophic niche of invasive brown and rainbow trout was as high as 26 and 51%, respectively. In contrast, the probability of spiders overlapping into the trophic niche of native fish was always less than 5%. Our results suggest that spiders share resources with invasive fish. In contrast, spiders had a low probability of trophic overlap with native fish indicating that the traits of invaders may be important in determining their influence on ecosystem subsidies. We have added to the growing body of evidence that invaders can have cross-ecosystem impacts and demonstrated that this can be due to niche overlap.

Combined treatment of amyloid-ß1₋42-stimulated bone marrow-derived dendritic cells plus splenocytes from young mice prevents the development of Alzheimer's disease in APPswe/PSENldE9 mice.

Anti-amyloid-ß (Aß) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aß immunotherapy. In this study, a combined treatment of Aß1₋42-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aß antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aß plaques. In conclusion, the Aß1₋42-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.

An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability.

INTRODUCTION: Gastrointestinal adverse effects contribute significantly to drug attrition as well as reduced patient compliance. Determination of gastrointestinal liability early in a compound's preclinical development would be a valuable tool. We evaluated the non-invasive faecal pellet method in the rat, assessed the feasibility of adding the endpoint to other study types and investigated correlation with the charcoal meal method. METHODS: Han Wistar rats, pair housed in metabolism cages, received a single dose of vehicle, atropine, bethanechol, loperamide or metoclopramide. The number, weight and appearance of pellets produced were assessed over 10 h and at 24 h post-dose. The endpoint was also added to a modified Irwin screen (testing atropine, theophylline, clonidine, amphetamine, baclofen or quinine) and a whole body plethysmography study (testing theophylline or bethanechol). Pellets were collected from home cages out to 4 h post-dose (Irwin) or following a 45 minutes plethysmography session. To assess correlation with stomach emptying and intestinal transit charcoal meal data was generated where published data was not available. RESULTS: Atropine decreased, while bethanechol and metoclopramide increased the number and weight of faecal pellets produced. Atropine produced darker, harder pellets and bethanechol lighter, softer pellets. Loperamide reduced pellet production at later time points only. Theophylline increased (Irwin and plethysmography) and atropine (Irwin) decreased pellet number and weight. Effects were maximal at the T(max) and detected in all study environments. Primary data generation was not affected by pellet collection. Pellet findings were generally comparable to charcoal meal transit data, with compounds showing an inhibition (atropine, loperamide, amphetamine, baclofen, clonidine, quinine) or stimulation (bethanechol) in both models. DISCUSSION: We have demonstrated that the faecal pellet method can detect expected reference compound induced changes in pellet transit. The technique is a useful non-invasive 'add-on' to other study types allowing gastrointestinal effects to be flagged earlier in preclinical development.

SAR development of a selective 5-HT1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis.

Incorporation of an SRI (serotonin reuptake inhibitor) pharmacophore into a selective 5-HT(1D) agonist has led to the discovery of a molecule having both 5-HT(1D) antagonist and SRI activity. RPS methodology was used to develop the SAR and identify potential approaches to reduce unwanted adrenergic alpha 1 and dopamine D(2) cross-reactivities.

Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression.

A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.