Transient ultrasound stimulation has lasting effects on neuronal excitability

Background Transcranial ultrasound stimulation can acutely modulate brain activity, but the lasting effects on neurons are unknown. Objective To assess the excitability profile of neurons in the hours following transient ultrasound stimulation. Methods Primary rat cortical neurons were stimulated with a 40 s, 200 kHz pulsed ultrasound stimulation or sham-stimulation. Intrinsic firing properties were investigated through whole-cell patch-clamp recording by evoking action potentials in response to somatic current injection. Recordings were taken at set timepoints following ultrasound stimulation: 0–2 h, 6–8 h, 12–14 h and 24–26 h. Transmission electron microscopy was used to assess synaptic ultrastructure at the same timepoints. Results In the 0–2 h window, neurons stimulated with ultrasound displayed an increase in the mean frequency of evoked action potentials of 32% above control cell levels (p = 0.023). After 4–6 h this increase was measured as 44% (p = 0.0043). By 12–14 h this effect was eliminated and remained absent 24–26 h post-stimulation. These changes to action potential firing occurred in conjunction with statistically significant differences between control and ultrasound-stimulated neurons in action potential half-width, depolarisation rate, and repolarisation rate, that were similarly eliminated by 24 h following stimulation. These effects occurred in the absence of alterations to intrinsic membrane properties or synaptic ultrastructure. Conclusion We report that stimulating neurons with 40 s of ultrasound enhances their excitability for up to 8 h in conjunction with modifications to action potential kinetics. This occurs in the absence of major ultrastructural change or modification of intrinsic membrane properties. These results can inform the application of transcranial ultrasound in experimental and therapeutic settings

High intensity interval training in handcycling: The effects of a 7 week training intervention in able-bodied men

Introduction: In lower body endurance training, quantities of both moderate intensity continuous training (MICT) and high intensity interval training (HIIT) can lead to an improved physiological capacity and performance. Limited research is available regarding the endurance and muscular capacity of the upper body, and how training contributes to improvements in performance capacity is still unknown. The aim of the current study was to evaluate the effects of HIIT and MICT on the physiological capacity and handcycling performance of able-bodied men in a well-controlled laboratory setting. Methods: Twenty four recreationally active men (22 ± 2 years; 1.84 ± 0.04 m; 79 ± 10 kg) were matched on incremental handcycling pre-test performance (peakPO) and then randomly assigned to HIIT, MICT, or a non-training control group (CON, 3 × n = 8). Participants in HIIT completed 14 interval training sessions, performing 4 × 4 min intervals at 85% heart rate reserve (%HRR), and seven continuous training sessions at 55 %HRR (every 2nd training session of the week). Participants in MICT performed 21 training sessions of 30 min at 55 %HRR. After the intervention, changes in peak oxygen uptake (peakVO2) and peak power output (peakPO) were compared within and between HIIT, MICT and CON. Results: The average external training load per training session did not differ between MICT and HIIT (p = 0.713). Improvements after HIIT in peakVO2 (22.2 ± 8.1%) and peakPO (47.1 ± 20.7%) were significantly larger compared with MICT and CON (p < 0.001). Improvements after MICT in peakVO2 (10.7 ± 12.9%) and peakPO (32.2 ± 8.1%) were higher compared to CON (p < 0.001). Higher improvement after HIIT occurred despite training 22% less time than MICT. No significant changes were found in CON. Discussion: As in lower body endurance sports, HIIT proved to be very effective in improving the physiological and performance capacity of upper body exercise. Whilst physiological capacity in both training groups improved significantly compared with CON, the present study shows that peakVO2 and peakPO improved more after HIIT than after MICT in able-bodied men. It is advised to include HIIT into training regimes of recreational and competitive handcyclists to improve the upper body endurance capacity

Studio Recital

Studio recital presenting the students of Charlotte Petersen. Featuring cellists and string ensembles.https://digitalcommons.usu.edu/music_programs/1124/thumbnail.jp

Toxicity of Sediment-Associated Pesticides to Chironomus dilutus and Hyalella azteca

Two hundred sediment samples were collected and their toxicity evaluated to aquatic species in a previous study in the agriculturally dominated Central Valley of California, United States. Pyrethroid insecticides were the main contributors to the observed toxicity. However, mortality in approximately one third of the toxic samples could not be explained solely by the presence of pyrethroids in the matrices. Hundreds of pesticides are currently used in the Central Valley of California, but only a few dozen are analyzed in standard environmental monitoring. A significant amount of unexplained sediment toxicity may be due to pesticides that are in widespread use that but have not been routinely monitored in the environment, and even if some of them were, the concentrations harmful to aquatic organisms are unknown. In this study, toxicity thresholds for nine sediment-associated pesticides including abamectin, diazinon, dicofol, fenpropathrin, indoxacarb, methyl parathion, oxyfluorfen, propargite, and pyraclostrobin were established for two aquatic species, the midge Chironomus dilutus and the amphipod Hyalella azteca. For midges, the median lethal concentration (LC50) of the pesticides ranged from 0.18 to 964 μg/g organic carbon (OC), with abamectin being the most toxic and propargite being the least toxic pesticide. A sublethal growth endpoint using average individual ash-free dry mass was also measured for the midges. The no–observable effect concentration values for growth ranged from 0.10 to 633 μg/g OC for the nine pesticides. For the amphipods, fenpropathrin was the most toxic, with an LC50 of 1–2 μg/g OC. Abamectin, diazinon, and methyl parathion were all moderately toxic (LC50s 2.8–26 μg/g OC). Dicofol, indoxacarb, oxyfluorfen, propargite, and pyraclostrobin were all relatively nontoxic, with LC50s greater than the highest concentrations tested. The toxicity information collected in the present study will be helpful in decreasing the frequency of unexplained sediment toxicity in agricultural waterways

Communication Structures of Supplemental Voluntary Kin Relationships

Although scholars have constructed typologies of voluntary (fictive) kin, few have considered challenges and opportunities of interaction and relationships between biolegal and voluntary kin. This study focused on one type of voluntary kin, supplemental voluntary kin, relationships that often arise because of differing values, underperformed roles, or physical distance from the biolegal family, and wherein relationships are maintained with biolegal and voluntary kin. We examined how these family systems are constructed via interactions in relational triads of “linchpin” persons between biolegal family and voluntary kin. From in-depth interviews with 36 supplemental voluntary kin, we examined themes in the linchpins’ discourse surrounding the interaction, rituals, and ideal relationship between biolegal family and voluntary kin. We constructed a typology of four relational triads representing these relationships: intertwined, limited, separate, and hostile. We describe the structure and communication within each type, and implications for helping families with these triangulated voluntary kin relationships

Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias. METHODS: We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10). RESULTS: There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity > 50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort. CONCLUSIONS: CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA

Homocitrullination of lysine residues mediated by myeloid derived suppressor cells in the tumour environment is a target for cancer immunotherapy

Background: Homocitrullination is the post translational modification of lysine that is recognized by T cells. Methods: This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and Bip and used HLA transgenic mice to assess immunogenicity by ELISpot assay. Vaccine efficacy was assessed in tumour therapy studies using HLA matched B16 melanoma expressing constitutive or IFNγ inducible MHC-II as represented by most human tumours. To determine the mechanism behind the therapy, immune cell infiltrates were analysed using flow cytometry and therapy studies in the presence of MPO inhibitor and T cell depletion performed. We assessed the T cell repertoire to homocitrullinated peptides in cancer patients and healthy donors using flow cytometry. Results: Homocitrulline peptide vaccination stimulated strong CD4 T cell responses and induced significant anti-tumour therapy in an established tumour model. The anti-tumour response was dependent upon CD4 T-cells and the effect was driven mainly via direct tumour recognition, as responses were only observed if the tumours were induced to express MHC-II. In vitro proliferation assays show that healthy donors and cancer patients have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by myeloperoxidase (MPO) inhibition reduced tumour therapy by the vaccine induced T cells (P=0.0018). Analysis of the tumour microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected B16 melanoma model showed MDSC infiltration. and was appropriate to see if the homocitrulline vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumour and likely reversed the immunosuppressive environment. Conclusion: We propose that MPO, potentially produced by MDSCs, catalyses the build-up of cyanate in the TME which diffuses into tumour cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumours containing high levels of MPO expressing MDSCs