Single-cell transcriptomics reveals prominent expression of IL-14, IL-18, and IL-32 in psoriasis.

RATIONALE: Psoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines. OBJECTIVES: Here we use single-cell transcriptomic analyses to identify relevant immune cell and nonimmune cell populations for an in-depth characterization of cell types and inflammatory mediators in this disease. METHODS: Psoriasis skin lesions of eight patients are analyzed using single-cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments. RESULTS: Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T-helper cells, dendritic cells, macrophages, and fibroblasts. Apart from well-known factors, IL-14 (TXLNA), IL-18, and IL-32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL-14, IL-18, and IL-32 was significantly higher in psoriatic skin compared with healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples, and in in vitro experiments. CONCLUSIONS: Taken together, we provide a differentiated view of psoriasis immune-cell phenotypes that support the role of IL-14, IL-18, and IL-32 in psoriasis pathogenesis.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ9-tetrahydrocannabinol (Δ9-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60%  of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ9-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ9-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ9-THC-induced reduction in oICSS and Δ9-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ9-THC-induced hypoactivity and catalepsy but failed to alter Δ9-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.

The role of limited access to students from more diverse nonfeeder medical schools in creating diversity inequities in neurosurgical residency.

OBJECTIVE: Improving racial/ethnic diversity in neurosurgery is a long-standing issue that needs to be addressed. The positive correlation between medical students with home neurosurgery programs and successful matriculation into neurosurgical residency is well documented. In this article, the authors explored the relationship between decreased racial/ethnic diversity in neurosurgery residency programs and racial/ethnic diversity in feeder medical schools. METHODS: The authors conducted a standardized review of the literature to evaluate potential causes for decreased racial/ethnic diversity within neurosurgery. Additionally, they calculated the average enrollment of Black/African American medical students at the top 5 neurosurgery feeder medical schools (determined by Antar et al. following the 2014-2020 match cycles) during the 2021-2022 school year and compared that with the enrollment at US allopathic medical schools with the highest enrollment of Black/African American students. They also compared these two groups in terms of how many students they sent into neurosurgery residency programs from 2014 to 2020. For each of these comparisons, the authors conducted a two-sample t-test to evaluate correlation between these two variables. RESULTS: There was significantly lower average enrollment of Black/African American students at the top 5 feeder medical programs into neurosurgery residency (80.6 ± 8.32) compared with the top 5 medical schools with Black/African American enrollment in the 2021-2022 school year (279 ± 122.00, p < 0.05). The authors also found a significant increase in the number of students entering neurosurgery residency programs between the top 5 feeder medical programs into neurosurgery residency (30.8 ± 6.06) and the top 5 medical programs for Black/African American enrollment (6 ± 6.16, p < 0.0001). CONCLUSIONS: In this paper, the authors examined, through a Black/African American lens, the role of racial/ethnic diversity in medical schools that historically send many students to neurosurgery residency. This study sought to provide insight into this problem and examine how Black/African American students from nonfeeder medical schools are disproportionately affected. The authors' findings suggest that the lack of Black/African American representation in neurosurgery is strongly correlated with the diversity efforts of medical schools. Lastly, the authors highlight the University of Miami's Summer Research Scholarship in Neurosurgery for Medical Students and other programs as potential solutions to combat the lack of racial/ethnic diversity in neurosurgery.

Anxiety in children and youth: Part 1-Diagnosis.

Anxiety disorders are the most common mental health concerns affecting Canadian children and adolescents. The Canadian Paediatric Society has developed two position statements that summarize current evidence regarding the diagnosis and management of anxiety disorders. Both statements offer evidence-informed guidance to support paediatric health care providers (HCPs) making decisions around the care of children and adolescents with these conditions. The objectives of Part 1, which focuses on assessment and diagnosis, are to: (1) review the epidemiology and clinical characteristics of anxiety disorders and (2) describe a process for assessment of anxiety disorders. Specific topics are reviewed, including prevalence, differential diagnosis, co-occurring conditions, and the process of assessment. Approaches are offered for standardized screening, history-taking, and observation. Associated features and indicators that distinguish anxiety disorders from developmentally appropriate fears, worries, and anxious feelings are considered. Note that when the word 'parent' (singular or plural) is used, it includes any primary caregiver and every configuration of family.

Clinical response of CARD14-associated papulosquamous eruption to an anti-interleukin-17A antibody.

Here we present another family with CARD14-associated papulosquamous eruption, which is characterized by mutations in CARD14 and skin lesions resembling psoriasis and pityriasis rubra pilaris. We show beneficial therapeutic response to anti-IL17A treatment in one patient and performed immunomonitoring of our patient, exhibiting enhanced pSTAT3 levels in T cells before treatment, which normalized after treatment. Together, our data support the pathogenic role of IL-17A in this disease, which might have consequences for future treatment decisions in this rare condition.

JAK-inhibitors in dermatology - small molecules, big impact? Overview of the mechanism of action, previous study results and potential adverse effects.

Numerous chronic inflammatory skin diseases are associated with the release of proinflammatory cytokines, which act via the intracellular JAK-STAT pathway. JAK inhibitors represent a promising, targeted therapeutic approach for cutaneous diseases. Impressive effects have been achieved with these agents in recent years. With the approval of the JAK-inhibitors Baricitinib, Upadacitinib and Abrocitinib, new systemic therapeutic agents are now available for moderate to severe atopic dermatitis. Other diseases in which the effectiveness of these small molecules could be shown are psoriasis, chilblain lupus, dermatomyositis, vitiligo and alopecia areata. As dermatologists, we are facing a whole series of new drug approvals. In this minireview we explain the active principles of JAK inhibitors and review study results in selected inflammatory skin diseases. Finally, possible side effects and initial as well as follow-up laboratory examinations for these drugs are discussed.

Comparative Apex Electrostatics of Atom Probe Tomography Specimens.

Rigorous electrostatic modeling of the specimen-electrode environment is required to better understand the fundamental processes of atom probe tomography (APT) and guide the analysis of APT data. We have developed a simulation tool that self-consistently solves the nonlinear electrostatic Poisson equation along with the mobile charge carrier concentrations and provides a detailed picture of the electrostatic environment of APT specimen tips. We consider cases of metals, semiconductors, and dielectrics. Traditionally in APT, and regardless of specimen composition, the apex electric field Eapex has been approximated by the relation Eapex=SV/(kr), which was originally derived for sharp, metallic conductors; we refer to this equation as the "k-factor approximation". Here, SV is tip-electrode bias, r is the radius of curvature of the tip apex, and k is a dimensionless fitting parameter with 1.5

Whole transcriptome RNA-Seq analysis reveals extensive cell type-specific compartmentalization in Volvox carteri.

BACKGROUND: One of evolution's most important achievements is the development and radiation of multicellular organisms with different types of cells. Complex multicellularity has evolved several times in eukaryotes; yet, in most lineages, an investigation of its molecular background is considerably challenging since the transition occurred too far in the past and, in addition, these lineages evolved a large number of cell types. However, for volvocine green algae, such as Volvox carteri, multicellularity is a relatively recent innovation. Furthermore, V. carteri shows a complete division of labor between only two cell types - small, flagellated somatic cells and large, immotile reproductive cells. Thus, V. carteri provides a unique opportunity to study multicellularity and cellular differentiation at the molecular level. RESULTS: This study provides a whole transcriptome RNA-Seq analysis of separated cell types of the multicellular green alga V. carteri f. nagariensis to reveal cell type-specific components and functions. To this end, 246 million quality filtered reads were mapped to the genome and valid expression data were obtained for 93% of the 14,247 gene loci. In the subsequent search for protein domains with assigned molecular function, we identified 9435 previously classified domains in 44% of all gene loci. Furthermore, in 43% of all gene loci we identified 15,254 domains that are involved in biological processes. All identified domains were investigated regarding cell type-specific expression. Moreover, we provide further insight into the expression pattern of previously described gene families (e.g., pherophorin, extracellular matrix metalloprotease, and VARL families). Our results demonstrate an extensive compartmentalization of the transcriptome between cell types: More than half of all genes show a clear difference in expression between somatic and reproductive cells. CONCLUSIONS: This study constitutes the first transcriptome-wide RNA-Seq analysis of separated cell types of V. carteri focusing on gene expression. The high degree of differential expression indicates a strong differentiation of cell types despite the fact that V. carteri diverged relatively recently from its unicellular relatives. Our expression dataset and the bioinformatic analyses provide the opportunity to further investigate and understand the mechanisms of cell type-specific expression and its transcriptional regulation.

Oxytocin opposes effects of bacterial endotoxin on ER-stress signaling in Caco2BB gut cells.

BACKGROUND: The neuropeptide neuromodulator and hormone oxytocin (OT) activates signaling pathways involved in mRNA translation in response to endoplasmic reticulum stress and reduces inflammation associated with experimental colitis in rats. The anti-inflammatory effects of OT may serve a vital role in the development, survival and function of newborn-type enterocytes during microbial gut colonization, which coincides with the milk suckling period when OT receptor expression peaks in the gut. Furthermore, mice deficient in the OT receptor have abnormal gut structure and function, underscoring OT's developmental importance. METHODS: We tested the effect of OT upon lipopolysaccharide (LPS)-induced markers of the inflammatory response in Caco2BB gut cells in vitro using automated immunocapillary electrophoresis. RESULTS: We demonstrate that OT suppresses NF-κB signaling and presumably inflammatory transcriptional programs, which are unleashed by LPS through the modulation of IκB. We show that OT counteracts LPS-elicited silencing of the unfolded protein response, a pathway limiting endoplasmic reticulum stress by suppressing protein translation. OT selectively activates dsRNA-activated kinase (PKR), X-box binding protein 1 (XBP1), immunoglobulin binding protein (BiP), A20 (TNFα-induced protein 3) and inositol requiring enzyme 1a (IRE1a). OT inactivates eukaryotic translation initiation factor 2a (eIF2a) without significant activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). CONCLUSIONS: Mild, preemptive stimulation of endoplasmic reticulum stress sensors by OT may precondition newborn enterocytes to resist apoptosis associated with inflammation and may support their differentiation and development by modulating cellular metabolism. GENERAL SIGNIFICANCE: OT may protect enterocytes and other cell types, such as neurons, from stress-related complications during postnatal development.

Colostrum oxytocin modulates cellular stress response, inflammation, and autophagy markers in newborn rat gut villi.

Little is known about the role of oxytocin (OT) in colostrum during early gut colonization. We previously showed that transient OT receptor (OTR) expression on newborn rat enterocytes coincides with the milk-suckling period, and that OT activates endoplasmic reticulum stress sensors in cultured enterocytes. Here, we explored whether colostrum-OT attenuates stress in newborn villi primed and unprimed by colostrum by measuring levels of stress markers including BiP (an ER chaperone), eIF2a (translation initiation factor), and pPKR (eIF2a kinase). We also measured two inflammation-signaling proteins NF-κB and its inhibitor IκB. To test the impact of colostrum on autophagy, we measured a marker of autophagy initiation, LC3A. Colostrum increased inactive p-eIF2a, p-PKR and IκB and reduced p-IκB, BiP and LC3A. LPS increased and OT decreased p-IkB. BiP (GRP78) was higher in unprimed than primed villi. Together, these data suggest that colostrum OT attenuates the impact of inflammation on postnatal gut villi and that OT enhances autophagy to protect against amino acid insufficiency-induced stress during the interval between birth and the first feeding.

Mental health problems in children with neuromotor disabilities.

Mental health in children with neuromotor disorders is part of a dynamic system, including medical and developmental domains, family, school and community. Presentations are often complex and multifactorial, requiring a broad, individualized approach. A narrative overview of mental health symptoms in children with neuromotor disabilities is provided, along with recommendations for their assessment and management using the WHO's International Classification of Functioning framework.

Chez les enfants ayant des troubles neuromoteurs, la santé mentale fait partie d'un système dynamique qui englobe les sphères de la médecine et du développement, la famille, l'école et la collectivité. Les présentations, souvent complexes et multifactorielles, nécessitent une approche globale, mais personnalisée. Les auteurs fournissent une description des symptômes de maladie mentale chez les enfants ayant des troubles neuromoteurs, de même que des recommandations sur leur évaluation et leur prise en charge à l'aide du cadre de la Classification internationale du fonctionnement de l'Organisation mondiale de la Santé.

The inducible nitA promoter provides a powerful molecular switch for transgene expression in Volvox carteri.

BACKGROUND: The multicellular green alga Volvox carteri represents an attractive model system to study various aspects of multicellularity like cellular differentiation, morphogenesis, epithelial folding and ECM biogenesis. However, functional and molecular analyses of such processes require a wide array of molecular tools for genetic engineering. So far there are only a limited number of molecular tools available in Volvox. RESULTS: Here, we show that the promoter of the V. carteri nitrate reductase gene (nitA) is a powerful molecular switch for induction of transgene expression. Strong expression is triggered by simply changing the nitrogen source from ammonium to nitrate. We also show that the luciferase (g-luc) gene from the marine copepod Gaussia princeps, which previously was engineered to match the codon usage of the unicellular alga Chlamydomonas reinhardtii, is a suitable reporter gene in V. carteri. Emitted light of the chemiluminescent reaction can be easily detected and quantified with a luminometer. Long-term stability of inducible expression of the chimeric nitA/g-luc transgenes after stable nuclear transformation was demonstrated by transcription analysis and bioluminescence assays. CONCLUSION: Two novel molecular tools for genetic engineering of Volvox are now available: the nitrate-inducible nitA promoter of V. carteri and the codon-adapted luciferase reporter gene of G. princeps. These novel tools will be useful for future molecular research in V. carteri.

Temperature dependence of the piezotronic effect in ZnO nanowires.

A comprehensive investigation was carried out on n-type ZnO nanowires for studying the temperature dependence of the piezotronic effect from 77 to 300 K. In general, lowering the temperature results in a largely enhanced piezotronic effect. The experimental results show that the behaviors can be divided into three groups depending on the carrier doping level or conductivity of the ZnO nanowires. For nanowires with a low carrier density (<10(17)/cm(3) at 77 K), the pieozotronic effect is dominant at low temperature for dictating the transport properties of the nanowires; an opposite change of Schottky barrier heights at the two contacts as a function of temperature at a fixed strain was observed for the first time. At a moderate doping (between 10(17)/cm(3) and 10(18)/cm(3) at 77 K), the piezotronic effect is only dominant at one contact, because the screening effect of the carriers to the positive piezoelectric polarization charges at the other end (for n-type semiconductors). For nanowires with a high density of carriers (>10(18)/cm(3) at 77 K), the piezotronic effect almost vanishes. This study not only proves the proposed fundamental mechanism of piezotronic effect, but also provides guidance for fabricating piezotronic devices.

Rapid response to dupilumab in an adult patient with eosinophilic esophagitis and allergic asthma.

BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus that belongs to the spectrum of Th2-mediated diseases. It is often associated with atopic comorbidities such as allergic asthma (AA) and poses a therapeutic challenge. CASE REPORT: We report on a 43-year-old patient with EoE and AA who did not show sufficient therapeutic control despite standard therapy. We started treatment with dupilumab, whereupon both EoE and AA rapidly improved and complete symptom resolution could be documented. The response to dupilumab was assessed by laboratory monitoring and gastroscopy, which showed a reduction of markers of type II inflammation and eosinophilic infiltrates in the esophagus. SUMMARY: Our report emphasizes the effective and safe use of dupilumab as a treatment option for EoE with concomitant beneficial effects on AA.

[Ultraviolet radiation in the pathogenesis of lupus erythematosus]. / UV-induzierte Pathogenese des Lupus erythematodes.

Photosensitivity represents an increased inflammatory reaction to sunlight, which can be observed particularly in the autoimmune disease lupus erythematosus. Cutaneous lupus erythematosus (CLE) can be provoked by ultraviolet (UV) radiation and can cause both acute, nonscarring and chronic, scarring skin changes. In systemic lupus erythematosus, on the other hand, provocation by UV radiation can lead to flare or progression of systemic involvement. The etiology of lupus erythematosus is multifactorial and includes genetic, epigenetic and immunologic mechanisms. In this review, we address the effect of UV radiation on healthy skin and photosensitive skin using the example of lupus erythematosus. We describe possible mechanisms of UV-triggered immune responses that could offer therapeutic approaches. Currently, photosensitivity can only be prevented by avoiding UV exposure itself. Therefore, it is important to better understand the underlying mechanisms in order to develop strategies to counteract the deleterious effects of photosensitivity.