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A total synthesis of the enantiopure syn,syn-tosyl-samroiyotmycin A, a C 2 -symmetric 20-membered antimalarial macrodiolide with syn,syn-configuration of the 8,24-dihydroxy-9,25-dimethyl units and it's enantiopure anti,anti-derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield via a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized seco-acids. By a similar approach we gained access to several samroiyotmycin analogues and precursors. Antimalarial activity was tested on multi-resistant (K1) and sensitive (Nf54) P. falciparum strains providing insight into structure activity relationships. Both tosyl-oxazol unit as well as the syn-configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, syn,syn-tosyl-samroiyotmycin A showed 3.4 times higher activities than the "tosyl-free" natural product., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

This study sought to develop a user-friendly decision-making tool to explore country-specific estimates for costs and economic consequences of different options for scaling screening and psychosocial interventions for women with common perinatal mental health problems in Malawi. We developed a simple simulation model using a structure and parameter estimates that were established iteratively with experts, based on published trials, international databases and resources, statistical data, best practice guidance and intervention manuals. The model projects annual costs and returns to investment from 2022 to 2026. The study perspective is societal, including health expenditure and productivity losses. Outcomes in the form of health-related quality of life are measured in Disability Adjusted Life Years, which were converted into monetary values. Economic consequences include those that occur in the year in which the intervention takes place. Results suggest that the net benefit is relatively small at the beginning but increases over time as learning effects lead to a higher number of women being identified and receiving (cost‑)effective treatment. For a scenario in which screening is first provided by health professionals (such as midwives) and a second screening and the intervention are provided by trained and supervised volunteers to equal proportions in group and individual sessions, as well as in clinic versus community setting, total costs in 2022 amount to US$ 0.66 million and health benefits to US$ 0.36 million. Costs increase to US$ 1.03 million and health benefits to US$ 0.93 million in 2026. Net benefits increase from US$ 35,000 in 2022 to US$ 0.52 million in 2026, and return-on-investment ratios from 1.05 to 1.45. Results from sensitivity analysis suggest that positive net benefit results are highly sensitive to an increase in staff salaries. This study demonstrates the feasibility of developing an economic decision-making tool that can be used by local policy makers and influencers to inform investments in maternal mental health., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Perinatal mental illness presents a significant health burden to both patients and families. Many factors are hypothesized to increase the incidence of perinatal depression and anxiety in the fetal surgical population, including uncertain fetal prognosis and inherent risks of surgery and preterm delivery., Objective: This study aimed to determine the incidence and disease course of postpartum depression and anxiety in the fetal surgery population., Study Design: A retrospective medical record review study was conducted of fetal surgery patients delivering between November 2016 and November 2021 at an academic level IV perinatal healthcare center. Demographics and surgical, obstetrical, and psychiatric diagnoses were abstracted. Standard descriptive analyses were performed., Results: Eligible patients were identified (N=119). Fetal surgery was performed at a mean gestational age of 22.8 weeks (standard deviation, 4.11). Laser ablation of placental anastomoses (n=51) and in utero myelomeningocele repair (n=22) were the most common procedures. Of 119 patients, 34 (28.6%) were diagnosed with preexisting depression or anxiety, with 19 (55.9%) and 17 (50.0%) on baseline medication for depression or anxiety, respectively, before surgery. Of 85 patients, 23 (27.1%) without a history of anxiety or depression had new identification of one or both after delivery. Of note, 2 patients experienced suicidal ideation after delivery. Of the 119 patients, 8 (6.7%) and 12 (10.1%) initiated a new psychiatric medication during or after pregnancy, respectively, and 19 (16.0%) received a therapy referral. Among patients with baseline anxiety or depression, 20 of 34 patients (58.8%) experienced an exacerbation after delivery, 9 of 34 patients (26.5%) were referred for therapy, 9 of 34 patients (26.5%) were changing dose or medication for anxiety, and 11 of 34 patients (32.4%) were changing dose or medication for depression. Of the 119 patients, 24 (20.2%) experienced new or worsening depression or anxiety after the standard 6-week postpartum visit., Conclusion: Among patients undergoing fetal surgery, a high incidence of postpartum depression and anxiety was identified, with most patients with prepregnancy anxiety or depression experiencing exacerbation after delivery. The timeframe to clinical presentation with depression or anxiety symptoms may be delayed beyond the traditional 6-week postpartum period and into the first postpartum year. This observation could be attributed to de novo postpartum exacerbation or a lack of standardized treatment approaches earlier in the disease course or antepartum period. Understanding effective longitudinal supportive interventions is an essential next step., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The dynamic immunological changes occurring throughout pregnancy are well-orchestrated and important for the success of the pregnancy. One of the key immune adaptations is the maternal immune tolerance towards the semi-allogeneic fetus. In this review, we provide a comprehensive overview of what is known about the innate and adaptive immunological changes in pregnancy and the role(s) of specific immune cells during physiological and pathological pregnancy. Alongside this, we provided details of remaining questions and challenges, as well as future perspectives for this growing field of research. Understanding the immunological changes that occur can inform potential strategies on treatments for the optimal health of the neonate and pregnant individual both during and after pregnancy.

Salmonella spp. express Salmonella pathogenicity island 1 Type III Secretion System 1 (T3SS-1) genes to mediate the initial phase of interaction with their host. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit population-level T3SS-1 gene expression. However, only a subset of Salmonella cells in a population express these genes, suggesting short-chain fatty acids could decrease T3SS-1 population-level expression by acting on per-cell expression or the proportion of expressing cells. Here, we combine single-cell, theoretical, and molecular approaches to address the effect of short-chain fatty acids on T3SS-1 expression. Our in vitro results show short-chain fatty acids do not repress T3SS-1 expression by individual cells. Rather, these compounds act to selectively slow the growth of T3SS-1-expressing cells, ultimately decreasing their frequency in the population. Further experiments indicate slowed growth arises from short-chain fatty acid-mediated depletion of the proton motive force. By influencing the T3SS-1 cell-type proportions, our findings imply gut microbial metabolites act on cooperation between the two cell types and ultimately influence Salmonella 's capacity to establish within a host., Competing Interests: The authors declare no competing interest.

Recent advances in high-throughput (HTP) automated mini-bioreactor systems have significantly improved development timelines for early-stage biologic programs. Automated platforms such as the ambr® 250 have demonstrated the ability, using appropriate scale-down approaches, to provide reliable estimates of process performance and product quality from bench to pilot scale, but data sets comparing to large-scale commercial processes (>10,000 L) are limited. As development moves toward late stages, specifically process characterization (PC), a qualified scale-down model (SDM) of the commercial process is a regulatory requirement as part of Biologics License Application (BLA)-enabling activities. This work demonstrates the qualification of the ambr® 250 as a representative SDM for two monoclonal antibody (mAb) commercial processes at scales >10,000 L. Representative process performance and product quality associated with each mAb were achieved using appropriate scale-down approaches, and special attention was paid to pCO 2 to ensure consistent performance and product quality. Principal component analysis (PCA) and univariate equivalence testing were utilized in the qualification of the SDM, along with a statistical evaluation of process performance and product-quality attributes for comparability. The ambr® 250 can predict these two commercial-scale processes (at center-point condition) for cell-culture performance and product quality. The time savings and resource advantages to performing PC studies in a small-scale HTP system improves the potential for the biopharmaceutical industry to get products to patients more quickly., (© 2019 American Institute of Chemical Engineers.)

The Target of Rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is inhibited by the drug rapamycin. In the budding yeast Saccharomyces cerevisiae, translational defects associated with TORC1 inactivation inhibit cell cycle progression at an early stage in G1, but little is known about the possible roles for TORC1 later in the cell cycle. We investigated the rapamycin-hypersensitivity phenotype of cells lacking the S phase cyclin Clb5 (clb5Δ) as a basis for uncovering novel connections between TORC1 and the cell cycle regulatory machinery. Dosage suppression experiments suggested that the clb5Δ rapamycin hypersensitivity reflects a unique Clb5-associated cyclin-dependent kinase (CDK) function that cannot be performed by mitotic cyclins and that also involves motor proteins, particularly the kinesin-like protein Kip3. Synchronized cell experiments revealed rapamycin-induced defects in pre-anaphase spindle assembly and S phase progression that were more severe in clb5Δ than in wild-type cells but no apparent activation of Rad53-dependent checkpoint pathways. Some rapamycin-treated cells had aberrant spindle morphologies, but rapamycin did not cause gross defects in the microtubule cytoskeleton. We propose a model in which TORC1 and Clb5/CDK act coordinately to promote both spindle assembly via a pathway involving Kip3 and S phase progression.