The role of tissue-resident memory T cells as mediators for response and toxicity in immunotherapy-treated melanoma—two sides of the same coin?

Tissue-resident memory T cells (TRM cells) have become an interesting subject of study for antitumor immunity in melanoma and other solid tumors. In the initial phases of antitumor immunity, they maintain an immune equilibrium and protect against challenges with tumor cells and the formation of primary melanomas. In metastatic settings, they are a prime target cell population for immune checkpoint inhibition (ICI) because they highly express inhibitory checkpoint molecules such as PD-1, CTLA-4, or LAG-3. Once melanoma patients are treated with ICI, TRM cells residing in the tumor are reactivated and expand. Tumor killing is achieved by secreting effector molecules such as IFN-γ. However, off-target effects are also observed. Immune-related adverse events, such as those affecting barrier organs like the skin, can be mediated by ICI-induced TRM cells. Therefore, a detailed understanding of this memory T-cell type is obligatory to better guide and improve immunotherapy regimens

Model for initiation of quality factor degradation at high accelerating fields in superconducting radio-frequency cavities

A model for the onset of the reduction in SRF cavity quality factor, the so-called Q-drop, at high accelerating electric fields is presented. Breakdown of the surface barrier against magnetic flux penetration at the cavity equator is considered to be the critical event that determines the onset of Q-drop. The worst case of triangular grooves with low field of first flux penetration Hp, as analyzed previously by Buzdin and Daumens, [1998 Physica C 294: 257], was adapted. This approach incorporates both the geometry of the groove and local contamination via the Ginzburg-Landau parameter kappa, so the proposed model allows new comparisons of one effect in relation to the other. The model predicts equivalent reduction of Hp when either roughness or contamination were varied alone, so smooth but dirty surfaces limit cavity performance about as much as rough but clean surfaces do. When in combination, contamination exacerbates the negative effects of roughness and vice-versa. To test the model with actual data, coupons were prepared by buffered chemical polishing and electropolishing, and stylus profilometry was used to obtain distributions of angles. From these data, curves for surface resistance generated by simple flux flow as a function of magnetic field were generated by integrating over the distribution of angles for reasonable values of kappa. This showed that combined effects of roughness and contamination indeed reduce the Q-drop onset field by ~30%, and that that contamination contributes to Q-drop as much as roughness. The latter point may be overlooked by SRF cavity research, since access to the cavity interior by spectroscopy tools is very difficult, whereas optical images have become commonplace. The model was extended to fit cavity test data, which indicated that reduction of the superconducting gap by contaminants may also play a role in Q-drop.Comment: 15 pages with 7 figure

First Observation of Self-Amplified Spontaneous Emission in a Free-Electron Laser at 109 nm Wavelength

We present the first observation of Self-Amplified Spontaneous Emission (SASE) in a free-electron laser (FEL) in the Vacuum Ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approx. 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width and intensity fluctuations all corroborate the existing models for SASE FELs.Comment: 6 pages including 6 figures; e-mail: [email protected]

Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy

Epilepsy diagnosis is complex, requires a team of specialists and relies on in-depth patient and family history, MRI-imaging and EEG monitoring. There is therefore an unmet clinical need for a non-invasive, molecular-based, biomarker to either predict the development of epilepsy or diagnose a patient with epilepsy who may not have had a witnessed seizure. Recent studies have demonstrated a role for microRNAs in the pathogenesis of epilepsy. MicroRNAs are short non-coding RNA molecules which negatively regulate gene expression, exerting profound influence on target pathways and cellular processes. The presence of microRNAs in biofluids, ease of detection, resistance to degradation and functional role in epilepsy render them excellent candidate biomarkers. Here we performed the first multi-model, genome-wide profiling of plasma microRNAs during epileptogenesis and in chronic temporal lobe epilepsy animals. From video-EEG monitored rats and mice we serially sampled blood samples and identified a set of dysregulated microRNAs comprising increased miR-93-5p, miR-142-5p, miR-182-5p, miR-199a-3p and decreased miR-574-3p during one or both phases. Validation studies found miR-93-5p, miR-199a-3p and miR-574-3p were also dysregulated in plasma from patients with intractable temporal lobe epilepsy. Treatment of mice with common anti-epileptic drugs did not alter the expression levels of any of the five miRNAs identified, however administration of an anti-epileptogenic microRNA treatment prevented dysregulation of several of these miRNAs. The miRNAs were detected within the Argonuate2-RISC complex from both neurons and microglia indicating these miRNA biomarker candidates can likely be traced back to specific brain cell types. The current studies identify additional circulating microRNA biomarkers of experimental and human epilepsy which may support diagnosis of temporal lobe epilepsy via a quick, cost-effective rapid molecular-based test

The Superconducting TESLA Cavities

The conceptional design of the proposed linear electron-positron collider TESLA is based on 9-cell 1.3 GHz superconducting niobium cavities with an accelerating gradient of Eacc >= 25 MV/m at a quality factor Q0 > 5E+9. The design goal for the cavities of the TESLA Test Facility (TTF) linac was set to the more moderate value of Eacc >= 15 MV/m. In a first series of 27 industrially produced TTF cavities the average gradient at Q0 = 5E+9 was measured to be 20.1 +- 6.2 MV/m, excluding a few cavities suffering from serious fabrication or material defects. In the second production of 24 TTF cavities additional quality control measures were introduced, in particular an eddy-current scan to eliminate niobium sheets with foreign material inclusions and stringent prescriptions for carrying out the electron-beam welds. The average gradient of these cavities at Q0 = 5E+9 amounts to 25.0 +- 3.2 MV/m with the exception of one cavity suffering from a weld defect. Hence only a moderate improvement in production and preparation techniques will be needed to meet the ambitious TESLA goal with an adequate safety margin. In this paper we present a detailed description of the design, fabrication and preparation of the TESLA Test Facility cavities and their associated components and report on cavity performance in test cryostats and with electron beam in the TTF linac. The ongoing R&D towards higher gradients is briefly addressed.Comment: 45 pages (Latex), 39 figures (Encapsulated Postscript), 53 Author

Action anticipation based on an agent's epistemic state in toddlers and adults

Do toddlers and adults engage in spontaneous Theory of Mind (ToM)? Evidence from anticipatory looking (AL) studies suggests that they do. But a growing body of failed replication studies raised questions about the paradigm’s suitability. In this multi-lab collaboration, we test the robustness of spontaneous ToM measures. We examine whether 18- to 27-month-olds’ and adults’ anticipatory looks distinguish between two basic forms of an agent’s epistemic states: knowledge and ignorance. In toddlers [ANTICIPATED n = 520 50% FEMALE] and adults [ANTICIPATED n = 408, 50% FEMALE] from diverse ethnic backgrounds, we found [SUPPORT/NO SUPPORT] for epistemic state-based action anticipation. Future research can probe whether this conclusion extends to more complex kinds of epistemic states, such as true and false beliefs

Physiological Observations and Omics to Develop Personalized Sensormotor Adaptability Countermeasures Using Bed Rest and Space Flight Data

Astronauts experience sensorimotor disturbances during the initial exposure to microgravity and during the re-adapation phase following a return to an earth-gravitational environment. These alterations may disrupt the ability to perform mission critical functional tasks requiring ambulation, manual control and gaze stability. Interestingly, astronauts who return from space flight show substantial differences in their abilities to readapt to a gravitational environment. The ability to predict the manner and degree to which individual astronauts would be affected would improve the effectiveness of countermeasure training programs designed to enhance sensorimotor adaptability. For such an approach to succeed, we must develop predictive measures of sensorimotor adaptability that will allow us to foresee, before actual space flight, which crewmembers are likely to experience the greatest challenges to their adaptive capacities. The goals of this project are to identify and characterize this set of predictive measures that include: 1) behavioral tests to assess sensory bias and adaptability quantified using both strategic and plastic-adaptive responses; 2) imaging to determine individual brain morphological and functional features using structural magnetic resonance imaging (MRI), diffusion tensor imaging, resting state functional connectivity MRI, and sensorimotor adaptation task-related functional brain activation; 3) genotype markers for genetic polymorphisms in Catechol-O-Methyl Transferase, Dopamine Receptor D2, Brain-derived neurotrophic factor and genetic polymorphism of alpha2-adrenergic receptor that play a role in the neural pathways underlying sensorimotor adaptation. We anticipate these predictive measures will be significantly correlated with individual differences in sensorimotor adaptability after long-duration space flight and an analog bed rest environment. We will be conducting a retrospective study leveraging data already collected from relevant ongoing/completed bed rest and space flight studies. These data will be combined with predictor metrics that will be collected prospectively - behavioral, brain imaging and genomic measures; from these returning subjects to build models for predicting post-mission (bed rest - non-astronauts or space flight - astronauts) adaptive capability as manifested in their outcome measures. Comparisons of model performance will allow us to better design and implement sensorimotor adaptability training countermeasures that are customized for each crewmember's sensory biases, adaptive capacity, brain structure and functional capacities, and genetic predispositions against decrements in post-mission adaptive capability. This ability will allow more efficient use of crew time during training and will optimize training prescriptions for astronauts to ensure expected outcomes

A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-\u3b2 signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-\u3b2 signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets

Recovery of Functional Sensorimotor Performance Following Long Duration Space Flight (Field Test)

No abstract availabl