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Lipoxins are an important class of pro-resolving mediators that play a crucial role in the resolution of inflammation. Thus, the synthesis of more metabolically stable synthetic lipoxin analogues is an area of significant interest. Herein the asymmetric synthesis of lipoxin A4 (LXA4) mimetics is reported in which the triene core of the molecule has been replaced by an aromatic sulfur-containing benzothiophene ring. The key steps in the synthesis included a Friedel–Crafts acylation, a Suzuki coupling between two upper and lower chain fragments, and a highly stereoselective Noyori transfer hydrogenation to set the stereochemistry of the alcohol at the benzylic position. A small library of benzothiophene-containing LXA4 analogues with further structural modifications was also successfully synthesised. These included analogues with phenoxy, p-fluorophenoxy, and p-trifluoromethylphenoxy substituents incorporated into the lower alkyl chain with the objective of providing enhanced metabolic stability by blocking ω-oxidation pathways.

NTCD-M3 is a novel live biotherapeutic, that has been shown in a Phase 2 clinical trial to prevent recurrence of C. difficile infection (CDI) when administered shortly after antibiotic treatment of the initial CDI episode. Fidaxomicin was not, however, in widespread use at the time this study was conducted.

The formation of pairs and trains of particles in inertial microfluidics is an important consideration for device design and applications, such as particle focusing and separation. We study the formation and stability of linear and staggered pairs of nearly rigid spherical particles of different sizes in a pressure-driven flow through a straight duct with a rectangular cross section under mild inertia. An in-house lattice-Boltzmann-immersed-boundary-finite-element code is used for three-dimensional simulations. We find that the stability and properties of pairs of heterogeneous particles strongly depend on particle sizes and their size ratio, while the formation of the pairs is also determined by the initial lateral position and the axial order of the particles. Our findings imply that perturbations of particle trajectories caused by other particles, as they are expected to happen even in dilute suspensions, can be important for the formation of stable pairs in inertial microfluidics.

The study of flow and particle dynamics in microfluidic cross-slot channels is of high relevance for lab-on-a-chip applications. In this work we investigate the dynamics of a rigid spherical particle in a cross-slot junction for a channel height-to-width ratio of 0.6 and at a Reynolds number of 120 for which a steady vortex exists in the junction area. Using an in-house immersed- boundary-lattice-Boltzmann code, we analyse the effect of the entry position of the particle in the junction and the particle size on the dynamics and trajectory shape of the particle. We find that the dynamics of the particle depends strongly on its lateral entry position in the junction and weakly on its vertical entry position; particles that enter close to the centre show trajectory oscillations. Larger particles have longer residence times in the junction and tend to oscillate less due to their confinement. Our work contributes to the understanding of the particle dynamics in intersecting flows and enables the design of optimised geometries for cytometry and particle manipulation.

Improvements to skill (and other characteristics) of quantitative probabilistic rainfall forecasting for weather and hydrological purposes are a high priority at the Australian Bureau of Meteorology (the Bureau), highlighted by a series of major floods in eastern Australia in early 2022. Post-processed ensemble numerical weather prediction (NWP) rainfall guidance is key to increasing forecast automation in routine conditions and providing better guidance for high impact rainfall events. The Bureau's existing NWP post-processing system has markedly increased weather rainfall forecast skill in recent years. However, to enable further forecast improvements and greater integration of rainfall processing for weather and hydrological purposes, a more general approach with fewer calibration steps was required. To these ends, we have developed 'RainForests': a multi-ensemble rainfall processing system, utilising gradient boosted decision tree (GBDT) ensembles for forecast calibration.RainForests is inspired by the ECPoint method of Hewson and Pillosu (2021). RainForests, like ECPoint, is a non-parametric and generally non-local method which uses decision trees to create situation-dependent error distributions for each input (analogous to an extension of Bayesian Joint Probabilities) that can be used to calibrate grid-scale rainfall guidance to point-scale.Key features of RainForests:Uses a series of GBDT ensembles to construct the error distribution in place of a single manually trained decision tree. This produces robust outputs which are near-continuous relative to inputs, allows for rapid retraining on new data or addition of feature variables, and utilises open source GBDT software. Uses additive error (delta = obs - forecast) in place of the forecast error ratio. This allows for calibration when forecast rainfall is zero. Error distributions vary with forecast rainfall amount (and other predictors). Models are trained and verified using both rain gauge and gauge-calibrated radar data, each of which have their uncertainties, strengths and weaknesses. Basic Bureau and RainForests QC is applied to the data to reduce gross errors. Error distributions are pooled for each NWP model (e.g. ECMWF ensemble), from around 100 individual input ensemble and deterministic ('ensemble of one') members in total. Resulting calibrated probability distributions for each model are then blended in probability space. Additionally, RainForests uses and contributes to capabilities in the Integrated Model post-PROcessing and VERification (IMPROVER) system being developed in collaboration with the UK Met Office.Initial RainForests outputs have comparable skill to the Bureau's existing post-processing system. Improvements are planned and will be reported on. It is also planned to provide calibrated rainfall ensemble members, derived from RainForests outputs, to downstream applications. This aims to support production of ensemble multiple-variable indices, hydrological applications and aggregation of rainfall forecasts in space and time.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions.SUMMARY STATEMENTThis study used a viral expression technique to disrupt synaptic output in the bed nucleus of the stria terminalis (BNST) of DBA/1 audiogenic seizure mice. Inactivating the BNST significantly improved survival following seizures and altered brainstem excitation/inhibition balance.

Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in samples from colorectal cancer patients, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.

We investigate the formation and stability of a pair of identical soft capsules in channel flow under mild inertia. We employ a combination of the lattice Boltzmann, finite element and immersed boundary methods to simulate the elastic particles in flow. Validation tests show excellent agreement with numerical results obtained by other research groups. Our results reveal new trajectory types that have not been observed for pairs of rigid particles. While particle softness increases the likelihood of a stable pair forming, the pair stability is determined by the lateral position of the particles. A key finding is that stabilisation of the axial distance occurs after lateral migration of the particles. During the later phase of pair formation, particles undergo damped oscillations that are independent of initial conditions. These damped oscillations are driven by a strong hydrodynamic coupling of the particle dynamics, particle inertia and viscous dissipation. While the frequency and damping coefficient of the oscillations depend on particle softness, the pair formation time is largely determined by the initial particle positions: the time to form a stable pair grows exponentially with the initial axial distance. Our results demonstrate that particle softness has a strong impact on the behaviour of particle pairs. The findings could have significant ramifications for microfluidic applications where a constant and reliable axial distance between particles is required, such as flow cytometry., 27 pages, 19 figures

Previously, we reported that distal Schaffer collaterals undergo biphasic changes in excitability during high-frequency stimulation (HFS), with an early hyper-excitability period followed by an excitability depression period. The extracellular divalent cations calcium and magnesium can regulate membrane excitability in neuronal tissue. Therefore, we hypothesized that altering the concentrations of extracellular calcium and magnesium would alter the biphasic excitability changes. We tested this hypothesis by recording distal Schaffer collateral fiber volleys in stratum radiatum of hippocampal area CA1 during 100 Hz HFS in artificial cerebral spinal fluid (ACSF) containing normal and altered concentrations of extracellular divalent cations. Our normal ACSF contained 2.0 mM calcium and 2.0 mM magnesium. We examined four solutions with altered divalent cation concentrations: 1) high-calcium/low-magnesium (3.8 mM/0.2 mM), 2) low-calcium/high-magnesium (0.2 mM/3.8 mM), 3) high-calcium/normal-magnesium (3.8 mM/2.0 mM), or 4) normal-calcium/high-magnesium (2.0 mM/10.0 mM), and assessed the effects on Schaffer collateral responses. Increasing or decreasing extracellular calcium enhanced or reduced (respectively) the early hyper-excitable period whereas increasing extracellular magnesium reduced the later excitability depression. Because these results might be explained by altered calcium influx through voltage-gated calcium (Ca(V)) channels, we tested Ca(V) blockers (ω–agatoxin IVA, ω-conotoxin-GVIA, cadmium), but observed no effects on responses during HFS. Some of the effects of altered divalent cation concentration may be explained by altered membrane surface charge. Although this mechanism does not completely explain our findings, calcium influx through Ca(V) channels is not required.

Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp

This study examines changes in synaptic transmission with progression of the chronic epileptic state. Male Sprague-Dawley rats (P40–45) were injected with either saline or pilocarpine. In rats injected with pilocarpine, status epilepticus ensued. Hippocampal slices were cut 20–60 days or 80–110 days post-treatment. Evoked and miniature EPSCs (mEPSCs) were recorded from CA1 pyramidal neurons using whole-cell voltage-clamp. Fiber volleys were also recorded from stratum radiatum. Evoked EPSCs from the pilocarpine-treated cohort showed enhanced amplitudes 20–60 days post-treatment compared to the saline-treated cohort, whereas mEPSCs recorded from the same age group showed no change in event frequency and a slight but significant decrease in mEPSC amplitude distribution. In contrast, comparing evoked EPSCs and mEPSCs recorded 80–110 days after treatment indicated reduced amplitudes from pilocarpine-treated animals compared to controls. mEPSC inter-event interval decreased. This could be explained by a partial depletion of the ready releasable pool of neurotransmitter vesicles in Schaffer collateral presynaptic terminals of the pilocarpine-treated rats. In both saline- and pilocarpine-treated cohorts, concomitant decreases in mEPSC amplitudes as time after treatment progressed suggest that age-related changes in CA1 circuitry may be partially responsible for changes in synaptic transmission that may influence the chronic epileptic state.

Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a ‘peak mean’ value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability ($${\hbox {h}}^{2}_{Ped} = 41\% \,[\hbox {P}=0.001]$$ h Ped 2 = 41 % [ P = 0.001 ] , $${\hbox {h}}^{2}_{SNP} = 39\%\, [\hbox {P}=0.002]$$ h SNP 2 = 39 % [ P = 0.002 ] ), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12–13%; $$\hbox {P}>0.05$$ P > 0.05 ). Heritability estimates of the geometric quantities alone; e.g. aortic diameter ($${\hbox {h}}^{2}_{Ped} = 29\%\, [\hbox {P}=0.009]$$ h Ped 2 = 29 % [ P = 0.009 ] , $${\hbox {h}}^{2}_{SNP} = 30\%\, [\hbox {P}=0.010]$$ h SNP 2 = 30 % [ P = 0.010 ] ), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.

This thesis examines the question of whether the first three centuries CE (the 'Roman Period') were witness to a rapid expansion of settlements and other sites in the Dakhleh Oasis of Egypt's Western Desert. I accomplish this through an examination of the archaeological evidence from the Oasis, primarily pottery, but also buildings and other forms of material remains. I conclude that economic, and probably demographic, growth is probable based on this evidence.

Introduction We evaluated volumetric tumor measurements and computed tomography texture analysis as prognostic indicators in patients with advanced non–small-cell lung cancer when compared with the unidimensional tumor size measurements used in Response Evaluation Criteria in Solid Tumors (RECIST). Patients and Methods In a retrospective review, computed tomography examinations in 77 patients with advanced non–small-cell lung cancer were evaluated before and after 2 cycles of chemotherapy. Baseline and changes in tumor diameter, volume, and texture were analyzed. Survival was analyzed with Cox regression analysis and Kaplan-Meier survival statistics. Results Cox regression analysis demonstrated that only change in tumor volume (exp(B) = 1.006; P = .02) and the initial sum of the largest target lesion diameters predicted survival (exp(B) = 1.013; P = .02). Kaplan-Meier statistics demonstrated that patients with an initial sum of the largest target lesion diameters less than 88 mm had median survival time of 587 days (95% confidence interval [CI], 269-905 days), compared with the survival of those with larger tumor burden of 407 days (95% CI, 235-579 days). Patients in whom tumor volume decreased by more than 29% had a median survival time of 622 days (95% CI, 448-796 days), compared with 305 days for those with less decrease (95% CI, 34-240 days). Conclusion This study demonstrates that change in lung tumor volume is a better marker of patient survival than change of unidimensional diameter measurements in our cohort. If confirmed in larger studies, this suggests that volumetry might improve clinical decision-making for individual patients and allow for faster assessment of new treatments.

The use of visible light to activate transition metal catalysts towards redox processes has transformed the way organic molecules can be constructed. Promotion of an electron to an excited state enables the generation of organic radicals through electron transfer to or from the metal complex, with the resulting radicals primed for reactions such as addition to carbon–carbon pi bonds. Despite advances in photoredox catalysis which have led to the discovery of numerous such methods for bond construction, this mild approach to the generation of free radicals has not been applied to the functionalisation of carbon–carbon sigmabonds. Here we report the first such use of photoredox catalysis to promote the addition of organic halides to the caged carbocycle [1.1.1]propellane; the products of this process are bicyclo[1.1.1]pentanes (BCPs), motifs that are of high importance as bioisosteres in the pharmaceutical industry, and in materials applications. The methodology shows broad substrate scope and functional group tolerance, and is applicable to both sp2and sp3carbon–halogen bonds, while the use of substrates containing alkene acceptors enables the single-step construction of polycyclic bicyclopentane products through cyclisation cascades. Finally, the potential to accelerate drug discovery is demonstrated through examples of late-stage bicyclopentylation to access natural product- and drug-like molecules.

Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photoredox catalysis to carbon-carbon π-bonds are well-established; however, this approach has yet to be applied to the functionalization of carbon-carbon σ-bonds. Here, we report the first such use of photoredox catalysis to promote the addition of organic halides to the carbocycle [1.1.1]propellane; the product bicyclo[1.1.1]pentanes (BCPs) are motifs of high importance in the pharmaceutical industry and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp2 carbon-halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of nonstabilized sp3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural productlike and druglike molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry and provide insight into the balance of radical stability and strain relief in the reaction cycle.

West Nile virus (WNV) spread to the US western plains states in 2003, when a significant mortality event attributed to WNV occurred in Greater Sage-grouse ( Centrocercus urophasianus ). The role of avian species inhabiting sagebrush in the amplification of WNV in arid and semiarid regions of the North America is unknown. We conducted an experimental WNV challenge study in Vesper Sparrows ( Pooecetes gramineus ), a species common to sagebrush and grassland habitats found throughout much of North America. We found Vesper Sparrows to be moderately susceptible to WNV, developing viremia considered sufficient to transmit WNV to feeding mosquitoes, but the majority of birds were capable of surviving infection and developing a humoral immune response to the WNV nonstructural 1 and envelope proteins. Despite clearance of viremia, after 6 mo, WNV was detected molecularly in three birds and cultured from one bird. Surviving Vesper Sparrows were resistant to reinfection 6 mo after the initial challenge. Vesper sparrows could play a role in the amplification of WNV in sagebrush habitat and other areas of their range, but rapid clearance of WNV may limit their importance as competent amplification hosts of WNV.

The current criterion for surgical intervention in abdominal aortic aneurysms, based upon a maximal aortic diameter, is considered conservative due to the high mortality rate in case of rupture. The research community is actively investigating the use of computational mechanics tools combined with patient-specific imaging to help identify more accurate criteria. Widespread uptake of a successful metric will however be limited by the need for computed tomography, which is at present the primary image extraction method on account of the location and complex shape of the aneurysms. The use of three-dimensional ultrasound as the scanning method is more attractive on account of increased availability, reduced cost and reduced risk to patients. The suitability of three-dimensional ultrasound is assessed for this purpose in the present work; computational fluid dynamics simulations were performed on geometries obtained from the same patient using both ultrasound and computed tomography. The influence of different smoothing algorithms is investigated in the geometry preparation stage and Taubin’s low-pass filter was found to best preserve geometry features. Laminar, Newtonian, steady-state simulation analysis identified haemodynamic characteristics to be qualitatively similar in terms of wall shear stress, velocity and vorticity. The study demonstrates the potential for three-dimensional ultrasound to be integrated into a more accessible patient-specific modelling tool able to identify the need for surgical intervention of abdominal aortic aneurysms.

Previous studies established different responses between proximal and distal portions of Schaffer collateral axons during high‐frequency and burst stimulation, with distal axons demonstrating biphasic changes in excitability (hyperexcitability followed by depression), but proximal axons showing only monophasic depression. Voltage‐dependent potassium (KV) channels are important determinants of axonal excitability, and block of KV channels can promote axon hyperexcitability. We therefore hypothesized that block of KV channels should lead to biphasic response changes in proximal Schaffer collaterals, like those seen in distal Schaffer collaterals. To test this hypothesis, we made extracellular recordings of distal Schaffer collateral responses in stratum radiatum of hippocampal area CA1 and proximal Schaffer collateral responses in stratum pyramidale of area CA3 during high‐frequency stimulation (HFS) at 100 Hz and burst stimulation at 200 msec intervals (5 Hz or theta frequency). We then applied a nonselective KV channel blocker, tetraethlylammonium (TEA, 10 mmol/L) or 4‐aminopyridine (4‐AP, 100 μmol/L), and assessed effects on Schaffer collateral responses. Surprisingly, block of KV channels had little or no effect on proximal Schaffer collateral responses during high‐frequency or burst stimulation. In contrast, KV channel blockade caused more rapid depression of distal Schaffer collateral responses during both high‐frequency and burst stimulation. These findings indicate that KV channels are important for maintaining distal, but not proximal, Schaffer collateral excitability during period of sustained high activity. Differential sensitivity of distal versus proximal Schaffer collaterals to KV channel block may reflect differences in channel density, diversity, or subcellular localization.

Axon conduction fidelity is important for signal transmission and has been studied in various axons, including the Schaffer collateral axons of the hippocampus. Previously, we reported that high-frequency stimulation (HFS) depresses Schaffer collateral excitability when assessed by whole-cell recordings from CA3 pyramidal cells but induces biphasic excitability changes (increase followed by decrease) in extracellular recordings of CA1 fiber volleys. Here, we examined responses from proximal (whole-cell or field-potential recordings from CA3 pyramidal cell somata) and distal (field-potential recordings from CA1 stratum radiatum) portions of the Schaffer collaterals during HFS and burst stimulation in hippocampal slices. Whole-cell and dual-field-potential recordings using 10–100-Hz HFS revealed frequency-dependent changes like those previously described, with higher frequencies producing more drastic changes. Dual-field-potential recordings revealed substantial differences in the response to HFS between proximal and distal regions of the Schaffer collaterals, with proximal axons depressing more strongly and only distal axons showing an initial excitability increase. Because CA3 pyramidal neurons normally fire in short bursts rather than long high-frequency trains, we repeated the dual recordings using 100–1,000-ms interval burst stimulation. Burst stimulation produced changes similar to those during HFS, with shorter intervals causing more drastic changes and substantial differences observed between proximal and distal axons. We suggest that functional differences between proximal and distal Schaffer collaterals may allow selective filtering of nonphysiological activity while maximizing successful conduction of physiological activity throughout an extensive axonal arbor.

Long-term potentiation (LTP) is often induced experimentally by continuous high-frequency afferent stimulation (HFS), typically at 100 Hz for 1 s. Induction of LTP requires postsynaptic depolarization and voltage-dependent calcium influx. Induction is more effective if the same number of stimuli are given as a series of short bursts rather than as continuous HFS, in part because excitatory postsynaptic potentials (EPSPs) become strongly depressed during HFS, reducing postsynaptic depolarization. In this study, we examined mechanisms of EPSP depression during HFS in area CA1 of rat hippocampal brain slices. We tested for presynaptic terminal vesicle depletion by examining minimal stimulation-evoked excitatory postsynaptic currents (EPSCs) during 100-Hz HFS. While transmission failures increased, consistent with vesicle depletion, EPSC latencies also increased during HFS, suggesting a decrease in afferent excitability. Extracellular recordings of Schaffer collateral fiber volleys confirmed a decrease in afferent excitability, with decreased fiber volley amplitudes and increased latencies during HFS. To determine the mechanism responsible for fiber volley changes, we recorded antidromic action potentials in single CA3 pyramidal neurons evoked by stimulating Schaffer collateral axons. During HFS, individual action potentials decreased in amplitude and increased in latency, and these changes were accompanied by a large increase in the probability of action potential failure. Time derivative and phase-plane analyses indicated decreases in both axon initial segment and somato-dendritic components of CA3 neuron action potentials. Our results indicate that decreased presynaptic axon excitability contributes to depression of excitatory synaptic transmission during HFS at synapses between Schaffer collaterals and CA1 pyramidal neurons.