Daily deviations in anger, guilt, and sympathy: a developmental diary study of aggression

With a diary study of 4- and 8-year-olds, we tested the association between daily deviations in anger and aggressive behavior, and whether this link was moderated by feelings of guilt and sympathy. Caregivers reported their children’s anger and aggression for 10 consecutive days (470 records; N = 80, 53 % girls). To calculate daily anger deviations from average anger levels, we subtracted each child’s average anger score (i.e., across 10 days) from his/her daily anger scores. Children reported their guilty feelings in response to vignettes depicting intentional harm, as well as their dispositional sympathy levels. Multilevel modeling indicated that within-child spikes in daily anger were associated with more aggression, above and beyond between-child differences in average anger levels. However, this association was weaker for children who reported higher levels of guilt. Sympathy did not moderate the anger-aggression link. We discuss potential implications for affective-developmental models of aggression and interventions that target anger-related aggression

Do moral emotions buffer the anger-aggression link in children and adolescents?

Given the prevalence of anger-related aggression in school and out-of-school contexts, research on counteracting the anger-aggression link in children and adolescents is likely to have implications for educators and practitioners. Here, we tested moral guilt and sympathy as potential moderators of the anger-aggression link in a sample of 4-, 8-, and 12-year-olds ( N= 242). Caregivers reported their children's aggression and anger levels with a questionnaire. Children reported their moral guilt (in response to vignettes depicting intentional harm) and sympathy levels in an interview. Moral guilt and sympathy interacted with anger in relation to aggression. Controlling for age, sex, socio-economic status, and inhibitory control, high anger was significantly related to high aggression, but not when children and adolescents had high guilt or sympathy. We discuss the potential roles of moral guilt and sympathy in mitigating the anger-aggression link

The physiological correlates of children's emotions in contexts of moral transgression

Heightened attention to sociomoral conflicts and arousal at the prospect of committing moral transgressions are thought to increase the likelihood of negatively valenced moral emotions (NVMEs; e.g., guilt) in children. Here, we tested this biphasic model of moral emotions with a psychophysiological framework. For a series of vignettes depicting moral transgressions, 5- and 8-year-olds (N = 138) were asked to anticipate their emotions as hypothetical victimizers. Their responses were coded for the presence and intensity of NVMEs. In addition, their heart rate (HR) was calculated for three intervals of interest: a baseline period, the presentation of vignettes, and the anticipation of emotions following vignettes. We used multilevel modeling to examine how change in children's HR across these intervals related to the intensity of their NVMEs. Those who experienced greater HR deceleration from baseline to vignettes and greater acceleration from vignettes to anticipated emotions reported more intense NVMEs. We discuss the potential attention- and arousal-related processes behind children's physiological reactivity and anticipated emotions in contexts of moral transgression

Children's autonomic nervous system activity while transgressing: relations to guilt feelings and aggression

Despite the well-established protective functions of guilt across childhood, its underlying physiological mechanisms have received little attention. We used latent difference scores (LDS) to model changes in children's (N = 267; 4- and 8-year-olds, 51% girls) skin conductance (SC) and respiratory sinus arrhythmia (RSA) while they imagined themselves committing antisocial acts. We then tested if their later reports of guilt, caregiver-reported aggressive behavior, and age were associated with these physiological changes. For 8-year-olds, changes in RSA leading up to and during transgressions were uniquely associated with the intensity of guilt feelings after transgressions. Eight-year-olds with higher guilt were rated lower in aggression, although children's physiology and aggression were not directly related. We discuss how fluctuations in physiology while transgressing may prepare children to mount adaptive guilt responses afterward and-more broadly-implications for understanding the mechanisms behind guilt and related behavior in early and middle childhood

Channel-Forming Activities in the Glycosomal Fraction from the Bloodstream Form of Trypanosoma brucei

Background: Glycosomes are a specialized form of peroxisomes (microbodies) present in unicellular eukaryotes that belong to the Kinetoplastea order, such as Trypanosoma and Leishmania species, parasitic protists causing severe diseases of livestock and humans in subtropical and tropical countries. The organelles harbour most enzymes of the glycolytic pathway that is responsible for substrate-level ATP production in the cell. Glycolysis is essential for bloodstream-form Trypanosoma brucei and enzymes comprising this pathway have been validated as drug targets. Glycosomes are surrounded by a single membrane. How glycolytic metabolites are transported across the glycosomal membrane is unclear. Methods/Principal Findings: We hypothesized that glycosomal membrane, similarly to membranes of yeast and mammalian peroxisomes, contains channel-forming proteins involved in the selective transfer of metabolites. To verify this prediction, we isolated a glycosomal fraction from bloodstream-form T.brucei and reconstituted solubilized membrane proteins into planar lipid bilayers. The electrophysiological characteristics of the channels were studied using multiple channel recording and single channel analysis. Three main channel-forming activities were detected with current amplitudes 70–80 pA, 20–25 pA, and 8–11 pA, respectively (holding potential +10 mV and 3.0 M KCl as an electrolyte). All channels were in fully open state in a range of voltages 6150 mV and showed no sub-conductance transitions. The channel with current amplitude 20–25 pA is anion-selective (P K+/P Cl2,0.31), while the other two types of channels are slightl

dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice

Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism. Here we tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue Scn1a haploinsufficiency in a mouse DS model and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system. We identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Nav1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, rescuing their ability to fire. To test the therapeutic potential of this approach, we delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recovered their firing ability, and febrile seizures were significantly attenuated. Our results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage

Abnormal RNA Stability in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA-binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in postmortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways

Neoantigen-specific T-cell immune responses: The paradigm of NPM1-mutated acute myeloid leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicat-ing persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients

The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches

Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cyto-kine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the re-lapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell im-pairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunother-apeutic approaches in these settings

Children’s Moral Emotion Attribution in the Happy Victimizer Task: The Role of Response Format

Previous research in the happy victimizer tradition indicated that preschool and early elementary-school children attribute positive emotions to the violator of a moral norm, whereas older children attribute negative moral emotions. Cognitive and motivational processes have been suggested as underlying this developmental shift. The current research investigated whether making the happy victimizer task less cognitively demanding, by providing children with alternative response formats, would increase children’s attribution of moral emotions and moral motivation. In Study 1, 93 4- to 7-year-old British children responded to the happy victimizer questions either in a normal condition (where they spontaneously pointed with a finger), a wait condition (where they had to wait before giving their answers), or an arrow condition (where they had to point with a paper arrow). In Study 2, 40 Spanish 4-year-old children responded in the happy victimizer task either in a normal or a wait condition. In both studies, participants’ attribution of moral emotions and moral motivation was significantly higher in the conditions with alternative response formats (wait, arrow) than in the normal condition. The role of cognitive abilities for emotion attribution in the happy victimizer task is discussed