Unraveling dystonia circuitry in rodent models using novel neuromodulation techniques

Dystonia is a network disorder presumed to result from abnormalities in multiple brain regions and in multiple cell populations. The specific pathomechanisms affecting the motor circuits in dystonia are, however, still largely unclear. Animal models for dystonia have long been used to advance our understanding on how specific brain regions and cell populations are involved in dystonia symptomatogenesis. Lesioning, pharmacological modulation and electrical stimulation paradigms were able to highlight that both the basal ganglia and the cerebellum are pathologically altered in these animal models for dystonia. Techniques such as optogenetics and chemogenetics now offer the opportunity for targeted modulation of brain regions and most importantly cell populations and circuits. This could not only allow for a better understanding of the dystonic brain, but potentially improve and expand treatment options. In hopes that the insights from these neuromodulation techniques will eventually translate into therapies, we aim to summarize and critically discuss the findings from different in vivo approaches used to dissect the network dysfunctions underlying dystonia

Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Portable microfluidic chip for detection of Escherichia coli in produce and blood

Pathogenic agents can lead to severe clinical outcomes such as food poisoning, infection of open wounds, particularly in burn injuries and sepsis. Rapid detection of these pathogens can monitor these infections in a timely manner improving clinical outcomes. Conventional bacterial detection methods, such as agar plate culture or polymerase chain reaction, are time-consuming and dependent on complex and expensive instruments, which are not suitable for point-of-care (POC) settings. Therefore, there is an unmet need to develop a simple, rapid method for detection of pathogens such as Escherichia coli. Here, we present an immunobased microchip technology that can rapidly detect and quantify bacterial presence in various sources including physiologically relevant buffer solution (phosphate buffered saline [PBS]), blood, milk, and spinach. The microchip showed reliable capture of E. coli in PBS with an efficiency of 71.8% ± 5% at concentrations ranging from 50 to 4,000 CFUs/mL via lipopolysaccharide binding protein. The limits of detection of the microchip for PBS, blood, milk, and spinach samples were 50, 50, 50, and 500 CFUs/mL, respectively. The presented technology can be broadly applied to other pathogens at the POC, enabling various applications including surveillance of food supply and monitoring of bacteriology in patients with burn wounds

Cardiac Involvement related to COVID-19 Infection and Vaccination in Children and Adolescents – Hong Kong's Perspective

Myocarditis and Pericarditis have many virological and immunological causes. This article described the SARS-CoV involvement to the heart in children and adolescents, also the entity Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but severe consequence of SARS-CoV2 infection. Hong Kong case definition of MIS-C was listed. The consensus from overseas experts was that MIS-C should be managed by multidisciplinary team with a structured long-term follow-up to monitor the functioning of various organs and ascertain the prognosis. The side effect mRNA vaccination causing myocarditis and pericarditis is also concern of paediatricians worldwide. Hong Kong published local epidemiology of acute myocarditis and pericarditis among adolescents following Comirnaty vaccination, the local and overseas data were used in fine-tuning the COVID vaccination program in children and adolescents. To prevent severe and fatal outcome of COVID-19 diseases, it is important to educate the public and to promote COVID-19 vaccination in the community, also to continue monitoring the safety of the available vaccines

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system

Lights and Shadows of Trait Emotional Intelligence: Its Mediating Role in the Relationship Between Negative Affect and State Anxiety in University Students

Nowadays, students are experiencing difficult and stressful situations due to the Global Pandemic Alert. This changing world can evoke negative emotions that have been traditionally linked to higher anxiety. Researches have been focused on the positive outcomes of trait emotional intelligence (TEI) preventing psychological disorders. However, the possibility that TEI might have a dark side has been neglected. Hence, this study aimed to explore the mediating effect of the three dimensions of TEI in the relationship between negative affect and anxiety symptoms among college students. Participants of this research were 467 undergraduates who completed an online self-reported questionnaire including the Positive and Negative Affect Schedule (PANAS; Watson et al., 1988), the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1970), and Trait Meta-Mood Scale (TMMS-24, Salovey et al., 1995). The global serial mediation model showed that the total amount of variance explained by the global model was 30.8% (R-2 = 0.31). Negative affectivity and age accounted for the 15.1% of state anxiety variance (R-2 = 0.15; c: B = 0.63, p < 0.001) while 15.7% of the variance of state anxiety was attributed to the direct or indirect effect of the three dimensions of TEI (R-2 = 0.16). Five indirect effects presented statistical significance (95% BootCI). The contrast analyses between mediators showed that three indirect effects had higher statistical weigh; the ability of negative affect to increase state anxiety through (i) emotional attention; (ii) emotional clarity, and (iii) serially through emotional clarity and mood repair. Our results indicated that students' negative emotions lead to higher emotional attention which in turn may enhance state anxiety in two ways: by a direct effect of emotional attention on state anxiety and by a serial effect through emotional clarity. Moreover, when negative affect is associated with lower emotional clarity, anxiety symptoms may also arise. However, when attention and clarity are connected, the negative effect is reversed into a positive one, decreasing state anxiety

The central role of natural killer cells in mediating acute myocarditis after mRNA COVID-19 vaccination

BACKGROUND: Vaccine-related acute myocarditis is recognized as a rare and specific vaccine complication following mRNA-based COVID-19 vaccinations. The precise mechanisms remain unclear. We hypothesized that natural killer (NK) cells play a central role in its pathogenesis. METHODS: Samples from 60 adolescents with vaccine-related myocarditis were analyzed, including pro-inflammatory cytokines, cardiac troponin T, genotyping, and immunophenotyping of the corresponding activation subsets of NK cells, monocytes, and T cells. Results were compared with samples from 10 vaccinated individuals without myocarditis and 10 healthy controls. FINDINGS: Phenotypically, high levels of serum cytokines pivotal for NK cells, including interleukin-1β (IL-1β), interferon α2 (IFN-α2), IL-12, and IFN-γ, were observed in post-vaccination patients with myocarditis, who also had high percentage of CD57 NK cells in blood, which in turn correlated positively with elevated levels of cardiac troponin T. Abundance of the CD57 NK subset was particularly prominent in males and in those after the second dose of vaccination. Genotypically, killer cell immunoglobulin-like receptor (KIR) KIR2DL5B(-)/KIR2DS3(+)/KIR2DS5(-)/KIR2DS4del(+) was a risk haplotype, in addition to single-nucleotide polymorphisms related to the NK cell-specific expression quantitative trait loci DNAM-1 and FuT11, which also correlated with cardiac troponin T levels in post-vaccination patients with myocarditis. CONCLUSION: Collectively, these data suggest that NK cell activation by mRNA COVID-19 vaccine contributed to the pathogenesis of acute myocarditis in genetically and epidemiologically vulnerable subjects

Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p = 0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth