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Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype ('Hap 3') that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for 'Hap 3' were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.

Human embryos utilise an array of processes to eliminate the very high prevalence of aneuploid cells in early embryo stages. Human embryo self-correction was recently demonstrated by their ability to eliminate/expel abnormal blastomeres as cell debris/fragments. A whole genome amplification study has demonstrated that 63.6% of blastocysts expelled cell debris with abnormal chromosomal rearrangements. Moreover, 55.5% of euploid blastocysts expel aneuploid debris, strongly suggesting that the primary source of cell free DNA in culture media is expelled aneuploid blastomeres and/or their fragments. Such a substantial ability to self-correct downstream from the blastocyststage, therefore, renders any chromosomal diagnosis at the blastocyststage potentially useless, and this, unfortunately, also must particularly include non-invasive PGT-A based on cell-free DNA in spent medium. High rates of false-positive diagnoses of human embryos often lead to non-use and/or disposal of embryos with entirely normal pregnancy potential. Before adopting yet another round of unvalidated PGT-A as a routine adjunct to IVF, we here present facts that deserve to be considered.

Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al. (2021) identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation.

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.

Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms' tumor 1-associated protein (WTAP), an adaptor for the N-6-methyladenosine (m(6)A) RNA methyltransferase complex. This regulation is mediated by 5' UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution m(6)A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m(6)A, and increased m(6)A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m(6)A RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.

The MED1 subunit has been shown to mediate ligand-dependent binding of the Mediator coactivator complex to multiple nuclear receptors, including the adipogenic PPAR gamma, and to play an essential role in ectopic PPAR gamma-induced adipogenesis of mouse embryonic fibroblasts. However, the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue have been unclear. Here, after establishing requirements for MED1, including specific domains, for differentiation of 3T3L1 cells and both primary white and brown preadipo-cytes, we used multiple genetic approaches to assess requirements for MED1 in adipocyte formation, maintenance, and function in mice. We show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodys-trophy. This work establishes MED1 as an essential transcriptional coactivator that ensures homeostatic functions of adipocytes.

Background Most patients with systemic lupus erythematosus (SLE) have IgG autoantibodies against the RNA-binding p40 (ORF1p) protein encoded by the L1 retroelement. This study tested if these autoantibodies are also present in children with pediatric SLE (pSLE) and if the p40 protein itself could be detected in immune cells. Methods Autoantibodies in the plasma of pSLE patients (n = 30), healthy children (n = 37), and disease controls juvenile idiopathic arthritis (JIA) (n = 32) and juvenile dermatomyositis (JDM) (n = 60), were measured by ELISA. Expression of p40 in immune cells was assessed by flow cytometry. Markers of neutrophil activation and death were quantitated by ELISA. Results IgG and IgA autoantibodies reactive with p40 were detected in the pSLE patients, but were low in healthy controls and in JIA or JDM. pSLE patients with active disease (13 of them newly diagnosed) had higher titers than the same patients after effective therapy (p = 0.0003). IgG titers correlated with SLEDAI (r = 0.65, p = 0.0001), ESR (r = 0.43, p = 0.02), and anti-dsDNA antibodies (r = 0.49, p < 0.03), and inversely with complement C3 (r = -0.55, p = 0.002) and C4 (r = -0.51, p = 0.006). p40 protein was detected in a subpopulation of CD66b(+) granulocytes in pSLE, as well as in adult SLE patients. Myeloperoxidase and neutrophil elastase complexed with DNA and the neutrophil-derived S100A8/A9 were elevated in plasma from pSLE patients with active disease and correlated with anti-p40 autoantibodies and disease activity. Conclusions Children with active SLE have elevated IgG and IgA autoantibodies against L1 p40, and this protein can be detected in circulating granulocytes in both pediatric and adult SLE patients. P40 expression and autoantibody levels correlate with disease activity. Markers of neutrophil activation and death also correlate with these autoantibodies and with disease activity, suggesting that neutrophils express L1 and are a source of p40.

Rationale: Immunization is a critical tool in the fight against infectious disease epidemics. Understanding hesitancy towards immunization is even more important nowadays, with the continuous threat of COVID-19 pandemic. Medical conspiracy beliefs, scientific skepticism, as well as low trust in governmental institutions, and evidence-based knowledge all have troubling effects on immunization. Objective: To examine how these factors cross-react to influence vaccine behavior against any vaccine preventable disease (VPD), we hypothesized a model consisting of the belief in conspiracy theories as the predictor, and as the mediators subjective and objective vaccine knowledge, and trust in the health care system and science. The model was tested by examining the vaccine intentions for the children and self for any VPD. Methods: Two separate studies were conducted on the representative samples of Serbian population; the first study investigated the intentions for child vaccination and the second study examined the vaccine intentions against any VPD, including adult vaccination. We used path analysis followed by logistic regression to analyze the data. Results: The results revealed high vaccine hesitancy motivated by the belief in the vaccine conspiracy theories, through its effect on reduced trust in medical science and institutions, and low objective vaccine knowledge. Conclusions: The results of this study may be used to implement appropriate policy changes and implementation of the public health campaigns to promote immunization with a wide range of vaccines against common diseases, such as measles, human papillomaviruses, or pertussis, and novel diseases, such as COVID.