Resourceful Actors, Not Weak Victims: Reframing Refugees’ Stigmatized Identity Enhances Long-Term Academic Engagement

Refugees suffer from a stigmatized identity portraying them as weak, unskilled victims. We developed a brief (~10-min) intervention that reframed refugees’ identity as being, by its very nature, a source of strength and skills. Reading and writing exercises, provided by a university, highlighted how refugees’ experiences helped them acquire skills such as perseverance and the ability to cope with adversity, which could help them succeed in a new country. In Experiment 1 (N = 93), the intervention boosted refugees’ (a) confidence in their ability to succeed at an imagined university and (b) challenge seeking: Participants were 70% more likely to take on an academic exercise labeled as difficult. In Experiment 2, the intervention, delivered to refugees entering an online university (N = 533), increased engagement in the online-learning environment by 23% over the subsequent year. There was also evidence of greater course completion. It is possible to reframe stigmatized individuals’ identity as inherently strong and resourceful, helping them put their strengths to use

Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction

Aza‐ and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six‐step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult‐to‐access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X‐ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 μm for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 μm).Six steps in one go! An unprecedented two component six‐step domino reaction, providing a straightforward and atom economical route to bioactive azabicycles and carbobicycles is presented. DFT calculations accounting for dispersion interactions revealed that chemoselectivity might result from small differences in transition state and reaction energies of the branching step. This reaction opens up a new vista of generating, in a single operation, new antivirals outperforming clinically used drugs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/1/chem201504798.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/2/chem201504798_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137557/3/chem201504798-sup-0001-misc_information.pd

Systematic analysis of the binding behaviour of UHRF1 towards different methyl- and carboxylcytosine modification patterns at CpG dyads

The multi-domain protein UHRF1 is essential for DNA methylation maintenance and binds DNA via a base-flipping mechanism with a preference for hemi-methylated CpG sites. We investigated its binding to hemi- and symmetrically modified DNA containing either 5-methylcytosine (mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), or 5-carboxylcytosine (caC). Our experimental results indicate that UHRF1 binds symmetrically carboxylated and hybrid methylated/carboxylated CpG dyads in addition to its previously reported substrates. Complementary molecular dynamics simulations provide a possible mechanistic explanation of how the protein could differentiate between modification patterns. First, we observe different local binding modes in the nucleotide binding pocket as well as the protein's NKR finger. Second, both DNA modification sites are coupled through key residues within the NKR finger, suggesting a communication pathway affecting protein-DNA binding for carboxylcytosine modifications. Our results suggest a possible additional function of the hemi-methylation reader UHRF1 through binding of carboxylated CpG sites. This opens the possibility of new biological roles of UHRF1 beyond DNA methylation maintenance and of oxidised methylcytosine derivates in epigenetic regulation

Functional Correction of Type VII Collagen Expression in Dystrophic Epidermolysis Bullosa

Functional defects in type VII collagen, caused by premature termination codons on both alleles of the COL7A1 gene, are responsible for the severe autosomal recessive types of the skin blistering disease, recessive dystrophic epidermolysis bullosa (RDEB). The full-length COL7A1 complementary DNA (cDNA) is about 9kb, a size that is hardly accommodated by therapeutically used retroviral vectors. Although there have been successful attempts to produce functional type VII collagen protein in model systems of RDEB, the risk of genetic rearrangements of the large repetitive cDNA sequence may hamper the clinical application of full-length COL7A1 cDNA in the human system. Therefore, we used trans-splicing to reduce the size of the COL7A1 transcript. Retroviral transduction of RDEB keratinocytes with a 3′ pre-trans-splicing molecule resulted in correction of full-length type VII collagen expression. Unlike parental RDEB keratinocytes, transduced cells displayed normal morphology and reduced invasive capacity. Moreover, transduced cells showed normal localization of type VII collagen at the basement membrane zone in skin equivalents, where it assembled into anchoring fibril-like structures. Thus, using trans-splicing we achieved correction of an RDEB phenotype in vitro, which marks an important step toward its application in gene therapy in vivo.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclu

Effectiveness of a large-scale distribution programme of free nicotine patches: a prospective evaluation

Abstract BACKGROUND: After an increase in cigarette taxes and implementation of smoke-free workplace legislation, the New York City Department of Health and Mental Hygiene, the New York State Department of Health, and the Roswell Park Cancer Institute undertook large-scale distribution of free nicotine replacement therapy (NRT). We did a 6 month follow-up survey to assess the success of this programme in improving smoking cessation on a population basis. METHODS: 34,090 eligible smokers who phoned a toll-free quitline were sent a 6-week course of nicotine patches (2 weeks each of 21 mg, 14 mg, and 7 mg per day). Brief follow-up counselling calls were attempted. At 6 months after treatment, we assessed smoking status of 1305 randomly sampled NRT recipients and a non-randomly selected comparison group of eligible smokers who, because of mailing errors, did not receive the treatment. NRT recipients were compared with local survey-derived data for heavy smokers in New York City. FINDINGS: An estimated 5% of all adults in New York City who smoked ten cigarettes or more daily received NRT; most (64%) recipients were non-white, foreign-born, or resided in a low-income neighbourhood. Of individuals contacted at 6 months, more NRT recipients than comparison group members successfully quit smoking (33%vs 6%, p\u3c0.0001), and this difference remained significant after adjustment for demographic factors and amount smoked (odds ratio 8.8, 95% CI 4.4-17.8). Highest quit rates were associated with those who were foreign born (87 [39%]), older than 65 years (40 [47%]), and smoked less than 20 cigarettes per day (116 [35%]). Those who received a counselling call were more likely to stop smoking than those who did not (246 [38%] vs 189 [27%], p=0.001). With the conservative assumption that every 6-month follow-up survey non-respondent continued to smoke, the stop rate among NRT recipients was 20%. At least 6038 successful quits were attributable to NRT receipt, and cost was 464 US dollars per quit. INTERPRETATION: Easy access to cessation medication for diverse populations could help many more smokers to stop

Antibacterial Activity of Phenolic Compounds Against the Phytopathogen Xylella fastidiosa

Xylella fastidiosa is a pathogenic bacterium that causes diseases in many crop species, which leads to considerable economic loss. Phenolic compounds (a group of secondary metabolites) are widely distributed in plants and have shown to possess antimicrobial properties. The anti-Xylella activity of 12 phenolic compounds, representing phenolic acid, coumarin, stilbene and flavonoid, was evaluated using an in vitro agar dilution assay. Overall, these phenolic compounds were effective in inhibiting X. fastidiosa growth, as indicated by low minimum inhibitory concentrations (MICs). In addition, phenolic compounds with different structural features exhibited different anti-Xylella capacities. Particularly, catechol, caffeic acid and resveratrol showed strong anti-Xylella activities. Differential response to phenolic compounds was observed among X. fastidiosa strains isolated from grape and almond. Elucidation of secondary metabolite-based host resistance to X. fastidiosa will have broad implication in combating X. fastidiosa-caused plant diseases. It will facilitate future production of plants with improved disease resistance properties through genetic engineering or traditional breeding approaches and will significantly improve crop yield

Novel role of a triglyceride-synthesizing enzyme:DGAT1 at the crossroad between triglyceride and cholesterol metabolism

AbstractAcyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in triacylglycerol (TG) biosynthesis. Here we show that genetic deficiency and pharmacological inhibition of DGAT1 in mice alters cholesterol metabolism. Cholesterol absorption, as assessed by acute cholesterol uptake, was significantly decreased in the small intestine and liver upon DGAT1 deficiency/inhibition. Ablation of DGAT1 in the intestine (I-DGAT1−/−) alone is sufficient to cause these effects. Consequences of I-DGAT1 deficiency phenocopy findings in whole-body DGAT1−/− and DGAT1 inhibitor-treated mice. We show that deficiency/inhibition of DGAT1 affects cholesterol metabolism via reduced chylomicron size and increased trans-intestinal cholesterol excretion. These effects are independent of cholesterol uptake at the apical surface of enterocytes but mediated through altered dietary fatty acid metabolism. Our findings provide insight into a novel role of DGAT1 and identify a pathway by which intestinal DGAT1 deficiency affects whole-body cholesterol homeostasis in mice. Targeting intestinal DGAT1 may represent a novel approach for treating hypercholesterolemia

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

Background Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. Methods MiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knock-out of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets. Results Several miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2. Conclusion The discovery that miR-10b mediates an aspect of cancer stemness – that of enhanced tumor cell adhesion, known to facilitate metastatic colonization – provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA

Enhanced Spike-specific, but attenuated Nucleocapsid-specific T cell responses upon SARS-CoV-2 breakthrough versus non-breakthrough infections

SARS-CoV-2 vaccine breakthrough infections frequently occurred even before the emergence of Omicron variants. Yet, relatively little is known about the impact of vaccination on SARS-CoV-2-specific T cell and antibody response dynamics upon breakthrough infection. We have therefore studied the dynamics of CD4 and CD8 T cells targeting the vaccine-encoded Spike and the non-encoded Nucleocapsid antigens during breakthrough infections (BTI, n=24) and in unvaccinated control infections (non-BTI, n=30). Subjects with vaccine breakthrough infection had significantly higher CD4 and CD8 T cell responses targeting the vaccine-encoded Spike during the first and third/fourth week after PCR diagnosis compared to non-vaccinated controls, respectively. In contrast, CD4 T cells targeting the non-vaccine encoded Nucleocapsid antigen were of significantly lower magnitude in BTI as compared to non-BTI. Hence, previous vaccination was linked to enhanced T cell responses targeting the vaccine-encoded Spike antigen, while responses against the non-vaccine encoded Nucleocapsid antigen were significantly attenuated