Investigating Bisphenol A Level Estimation and Possible Effects on Fetal Biometry

Background: The estrogenic endocrine disruptor bisphenol A (BPA), which is used in plastics and resins, may have an impact on the fetus’s growth and development and can modify postnatal development. This study aims to assess how bisphenol A affects fetal biometry.Methods: This analytical cross-sectional study included 384 healthy Egyptian women in their third trimester during childbearing (15–44 years). They were selected from the outpatient Clinic of Obstetrics and Gynecology at Kasr El-Ainy Hospital, Cairo, Egypt. Fetal biometry was measured and urine samples were collected to estimate BPA levels. Results: Fetal weight, centile, and corrected bisphenol A levels were significantly higher in the studied age groups (P<0.05). A significant positive correlation was found between BPA level and estimated fetal weight, centile, and age of the mother per year. On the other hand, no significant difference was detected with other fetal measurements in the studied groups (P>0.05).Conclusion: Fetal exposure to BPA is associated with higher estimated fetal weight and centile commonly in the maternal age range 25 to 35 years

Validation of the Chinese version of the "Mood Disorder Questionnaire" for screening bipolar disorder among patients with a current depressive episode

<p>Abstract</p> <p>Background</p> <p>The Mood Disorder Questionnaire (MDQ) is a well-recognized screening tool for bipolar disorder, but its Chinese version needs further validation. This study aims to measure the accuracy of the Chinese version of the MDQ as a screening instrument for bipolar disorder (BPD) in a group of patients with a current major depressive episode.</p> <p>Methods</p> <p>142 consecutive patients with an initial DSM-IV-TR diagnosis of a major depressive episode were screened for BPD using the Chinese translation of the MDQ and followed up for one year. The final diagnosis, determined by a special committee consisting of three trained senior psychiatrists, was used as a 'gold standard' and ROC was plotted to evaluate the performance of the MDQ. The optimal cut-off was chosen by maximizing the Younden's index.</p> <p>Results</p> <p>Of the 142 patients, 122 (85.9%) finished the one year follow-up. On the basis of a semi-structured clinical interview 48.4% (59/122) received a diagnosis of unipolar depression (UPD), 36.9% (45/122) BPDII and 14.8% (18/122) BPDI. At the end of the one year follow-up,9 moved from UPD to BPD, 2 from BPDII to UPD, 1 from BPDII to BPDI, the overall rate of initial misdiagnosis was 16.4%. MDQ showed a good accuracy for BPD: the optimal cut-off was 4, with a sensitivity of 0.72 and a specificity of 0.73. When BPDII and BPDI were calculated independently, the optimal cut-off for BPDII was 4, with a sensitivity of 0.70 and a specificity of 0.73; while the optimal cut-off for BPDI was 5, with a sensitivity of 0.67 and a specificity of 0.86.</p> <p>Conclusions</p> <p>Our results show that the Chinese version of MDQ is a valid tool for screening BPD in a group of patients with current depressive episode on the Chinese mainland.</p

Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from a

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

The SUMO Isopeptidase Ulp2p Is Required to Prevent Recombination-Induced Chromosome Segregation Lethality following DNA Replication Stress

SUMO conjugation is a key regulator of the cellular response to DNA replication stress, acting in part to control recombination at stalled DNA replication forks. Here we examine recombination-related phenotypes in yeast mutants defective for the SUMO de-conjugating/chain-editing enzyme Ulp2p. We find that spontaneous recombination is elevated in ulp2 strains and that recombination DNA repair is essential for ulp2 survival. In contrast to other SUMO pathway mutants, however, the frequency of spontaneous chromosome rearrangements is markedly reduced in ulp2 strains, and some types of rearrangements arising through recombination can apparently not be tolerated. In investigating the basis for this, we find DNA repair foci do not disassemble in ulp2 cells during recovery from the replication fork-blocking drug methyl methanesulfonate (MMS), corresponding with an accumulation of X-shaped recombination intermediates. ulp2 cells satisfy the DNA damage checkpoint during MMS recovery and commit to chromosome segregation with similar kinetics to wild-type cells. However, sister chromatids fail to disjoin, resulting in abortive chromosome segregation and cell lethality. This chromosome segregation defect can be rescued by overproducing the anti-recombinase Srs2p, indicating that recombination plays an underlying causal role in blocking chromatid separation. Overall, our results are consistent with a role for Ulp2p in preventing the formation of DNA lesions that must be repaired through recombination. At the same time, Ulp2p is also required to either suppress or resolve recombination-induced attachments between sister chromatids. These opposing defects may synergize to greatly increase the toxicity of DNA replication stress