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Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.
Rationale
While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation.
Objective
Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene.
Results
Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner.
Conclusions
Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.
Background. Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years. Methods. Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time. Results. Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004. Conclusions. A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care.
The novel BackHome system offers individuals with disabilities a range of useful services available via brain-computer interfaces (BCIs), to help restore their independence. This is the time such technology is ready to be deployed in the real world, that is, at the target end users’ home. This has been achieved by the development of practical electrodes, easy to use software, and delivering telemonitoring and home support capabilities which have been conceived, implemented, and tested within a user-centred design approach. The final BackHome system is the result of a 3-year long process involving extensive user engagement to maximize effectiveness, reliability, robustness, and ease of use of a home based BCI system. The system is comprised of ergonomic and hassle-free BCI equipment; one-click software services for Smart Home control, cognitive stimulation, and web browsing; and remote telemonitoring and home support tools to enable independent home use for nonexpert caregivers and users. BackHome aims to successfully bring BCIs to the home of people with limited mobility to restore their independence and ultimately improve their quality of life.
Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo) phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13\(^{-/-}\) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13\(^{-/-}\) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.
Many fractional quantum Hall wave functions are known to be unique highest-density zero modes of certain "pseudopotential" Hamiltonians. While a systematic method to construct such parent Hamiltonians has been available for the infinite plane and sphere geometries, the generalization to manifolds where relative angular momentum is not an exact quantum number, i.e., the cylinder or torus, remains an open problem. This is particularly true for non-Abelian states, such as the Read-Rezayi series (in particular, the Moore-Read and Read-Rezayi Z\(_3\) states) and more exotic nonunitary (Haldane-Rezayi and Gaffnian) or irrational (Haffnian) states, whose parent Hamiltonians involve complicated many-body interactions. Here, we develop a universal geometric approach for constructing pseudopotential Hamiltonians that is applicable to all geometries. Our method straightforwardly generalizes to the multicomponent SU(n) cases with a combination of spin or pseudospin (layer, subband, or valley) degrees of freedom. We demonstrate the utility of our approach through several examples, some of which involve non-Abelian multicomponent states whose parent Hamiltonians were previously unknown, and we verify the results by numerically computing their entanglement properties.
Background
Fabry-associated pain may be the first symptom of Fabry disease (FD) and presents with a unique phenotype including mostly acral burning triggerable pain attacks, evoked pain, pain crises, and permanent pain. We recently developed and validated the first Fabry Pain Questionnaire (FPQ) for adult patients. Here we report on the validation of the self-administered version of the FPQ that no longer requires a face-to-face interview but can be filled in by the patients themselves allowing more flexible data collection.
Methods
At our Würzburg Fabry Center for Interdisciplinary Treatment, Germany, we have developed the self-administered version of the FPQ by adapting the questionnaire to a self-report version. To do this, consecutive Fabry patients with current or past pain history (n = 56) were first interviewed face-to-face. Two weeks later patients’ self-reported questionnaire results were collected by mail (n = 55). We validated the self-administered version of the FPQ by assessing the inter-rater reliability agreement of scores obtained by supervised administration and self-administration of the FPQ.
Results
The FPQ contains 15 questions on the different pain phenotypes, on pain development during life with and without therapy, and on impairment due to pain. Statistical analysis showed that the majority of questions were answered in high agreement in both sessions with a mean AC1-statistic of 0.857 for 55 nominal-scaled items and a mean ICC of 0.587 for 9 scores.
Conclusions
This self-administered version of the first pain questionnaire for adult Fabry patients is a useful tool to assess Fabry-associated pain without a time-consuming face-to-face interview but via a self-reporting survey allowing more flexible usage.
Background
In this study, we evaluated electrooculography (EOG), an eye tracker and an auditory brain-computer interface (BCI) as access methods to augmentative and alternative communication (AAC). The participant of the study has been in the locked-in state (LIS) for 6 years due to amyotrophic lateral sclerosis. He was able to communicate with slow residual eye movements, but had no means of partner independent communication. We discuss the usability of all tested access methods and the prospects of using BCIs as an assistive technology.
Methods
Within four days, we tested whether EOG, eye tracking and a BCI would allow the participant in LIS to make simple selections. We optimized the parameters in an iterative procedure for all systems.
Results
The participant was able to gain control over all three systems. Nonetheless, due to the level of proficiency previously achieved with his low-tech AAC method, he did not consider using any of the tested systems as an additional communication channel. However, he would consider using the BCI once control over his eye muscles would no longer be possible. He rated the ease of use of the BCI as the highest among the tested systems, because no precise eye movements were required; but also as the most tiring, due to the high level of attention needed to operate the BCI.
Conclusions
In this case study, the partner based communication was possible due to the good care provided and the proficiency achieved by the interlocutors. To ease the transition from a low-tech AAC method to a BCI once control over all muscles is lost, it must be simple to operate. For persons, who rely on AAC and are affected by a progressive neuromuscular disease, we argue that a complementary approach, combining BCIs and standard assistive technology, can prove valuable to achieve partner independent communication and ease the transition to a purely BCI based approach. Finally, we provide further evidence for the importance of a user-centered approach in the design of new assistive devices.