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Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

Depression is apparently the most common psychiatric disease among the mood disorders affecting about 10% of the adult population. The etiology and pathogenesis of depression are still poorly understood. Hence, as for most human diseases, animal models can help us understand the pathogenesis of depression and, more importantly, may facilitate the search for therapy. In this review we first describe the more common tests used for the evaluation of depressive-like symptoms in rodents. Then we describe different models of depression and discuss their strengths and weaknesses. These models can be divided into several categories: genetic models, models induced by mental acute and chronic stressful situations caused by environmental manipulations (i.e., learned helplessness in rats/mice), models induced by changes in brain neuro-transmitters or by specific brain injuries and models induced by pharmacological tools. In spite of the fact that none of the models completely resembles human depression, most animal models are relevant since they mimic many of the features observed in the human situation and may serve as a powerful tool for the study of the etiology, pathogenesis and treatment of depression, especially since only few patients respond to acute treatment. Relevance increases by the fact that human depression also has different facets and many possible etiologies and therapies.

Background Overuse of short-acting beta-2 agonists (SABA), which do not treat the underlying inflammation of asthma, is linked to poor clinical outcomes such as increased exacerbation risk. This study, as part of the SABINA program, estimated the prevalence of SABA overuse and associated variables in outpatients in Germany. Methods This retrospective study used anonymized electronic healthcare data from the Disease Analyzer database (IQVIA). A total of 15,640 patients aged ≥ 12 years with asthma who received ≥ 1 SABA prescription(s) between July 2017 and June 2018 in 924 general physician and 22 pneumologist (PN) practices were included. SABA overuse was defined as ≥ 3 prescribed inhalers (~ 200 puffs each) during the study period. The associations between SABA overuse and physician specialty, Global Initiative for Asthma (GINA) steps (based on asthma medications), age, sex, and inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) use were estimated using multivariable regression for patients with probable moderate (GINA step 2) and probable severe (GINA steps 3–5) asthma. Results Annually, 36% of all patients (GINA steps 1–5) in general and 38% in PN practices received ≥ 3 SABA inhalers. The risk of SABA overuse was 14% higher in patients treated by a general practitioner vs. a PN; 34% and 85% higher in GINA steps 4 and 5, respectively, vs. GINA step 3; and 40% higher in male vs. female patients. Conclusions SABA overuse is prevalent among patients with asthma across all GINA steps in Germany, which may indicate suboptimal asthma control. Further studies are needed to investigate the reasons behind SABA overuse.

In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of ”epigenetic human diseases”.

New media are an important resource for the political participation of marginalized groups. However, there is still a lack of knowledge about the factors that influence whether this opportunity is used. Influencing factors emerge from both the Civic Voluntarism Model and previous research on migrants’ political activity. Using data collected in 2019/2020 from 486 refugees living in Bavaria, we estimate linear probability models to investigate facilitating factors for the use of new media for political participation. The analysis shows that refugees in Germany who inform themselves about politics online tend to be predominantly male, higher educated, and politically involved. Language skills and the duration of stay also appear to be important. For the expression of one’s political opinion online, gender and language skills have an impact, but informing oneself about German politics, political interest, and offline political activity in Germany are the most relevant factors. This indicates that there is a close link between on- und offline activity. However, using the internet requires particular resources, so that people with lower language skills, for example, are particularly disadvantaged.

Decades ago, Aharonov and Bohm showed that electrons are affected by electromagnetic potentials in the absence of forces due to fields. Zeilinger’s theorem describes this absence of classical force in quantum terms as the “dispersionless” nature of the Aharonov-Bohm effect. Shelankov predicted the presence of a quantum “force” for the same Aharonov-Bohm physical system as elucidated by Berry. Here, we report an experiment designed to test Shelankov’s prediction and we provide a theoretical analysis that is intended to elucidate the relation between Shelankov’s prediction and Zeilinger’s theorem. The experiment consists of the Aharonov-Bohm physical system; free electrons pass a magnetized nanorod and far-field electron diffraction is observed. The diffraction pattern is asymmetric confirming one of Shelankov’s predictions and giving indirect experimental evidence for the presence of a quantum “force”. Our theoretical analysis shows that Zeilinger’s theorem and Shelankov’s result are both special cases of one theorem. The dispersionless nature of Aharonov-Bohm effect is still debated. Here, the authors show an asymmetry in the diffraction pattern of an electron beam induced and controlled by an inaccessible magnetic flux, which means electrons behave “as if” an Aharonov-Bohm “force” was present.

Two-color multiphoton emission from polycrystalline tungsten nanotips has been demonstrated using two-color laser fields. The two-color photoemission is assisted by a three-photon multicolor quantum channel, which leads to a twofold increase in quantum efficiency. Weak-field control of two-color multiphoton emission was achieved by changing the efficiency of the quantum channel with pulse delay. The result of this study complements two-color tunneling photoemission in strong fields, and has potential applications for nanowire-based photonic devices. Moreover, the demonstrated two-color multiphoton emission may be important for realizing ultrafast spin-polarized electron sources via optically injected spin current.

Recently, initial studies describing the use of multicolor fluorescence in situ hybridization (FISH) for classifying melanocytic skin lesions have been published demonstrating a high sensitivity and specificity in discriminating melanomas from nevi. However, the majority of these studies included neither histologically ambiguous lesions nor a clinical long-term follow up. This study was undertaken to validate a special multicolor FISH test in histologically ambiguous melanocytic skin lesions with known clinical long-term follow up. FISH was scored by three independent pathologists in a series of 22 melanocytic skin lesions, including 12 ambiguous cases using four probes targeting chromosome 6p25, centromere 6, 6q23, and 11q13. The FISH results were compared with array comparative genomic hybridization data and correlated to the clinical long-term follow up (mean: 65 months). Pair-wise comparison between the interpretations of the observers showed a moderate to substantial agreement ( κ 0.47–0.61). Comparing the FISH results with the clinical behavior reached an overall sensitivity of 60% and a specificity of 50% ( χ 2 =0.25; P =0.61) for later development of metastases. Comparison of array comparative genomic hybridization data with FISH analyses did not yield significant results but array comparative genomic hybridization data demonstrated that melanocytic skin lesions with the development of metastases showed significantly more chromosomal aberrations ( P <0.01) compared with melanocytic skin lesions without the development of metastases. The FISH technique with its present composition of locus-specific probes for RREB1/MYB and CCND1 did not achieve a clinically useful sensitivity and specificity. However, a reassessment of the probes and better standardization of the method may lead to a valuable diagnostic tool.

The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8-DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.