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Over two growing seasons, a chloroplast localized synthetic glycolate metabolic pathway expressed in potato, enhanced tuber biomass. We confirmed that this yield benefit did not come at the cost of tuber quality. In 2022, after two early season natural heatwaves, we observed enhanced daily carbon assimilation rates and increased photosynthetic capacity, with transformed plants having up to 23% higher Vcmax and 13% higher Jmax during tuber bulking stages, indicating that transformed plants were better able to withstand growing season heatwaves than untransformed controls. The increases in photosynthetic capacity and potato tuber mass after early season heatwaves were greater than in seasons without heatwaves and present the AP3 pathway as a promising avenue for yield increases in the face of forecast increased intensity and duration of heatwave events as a result of global warming. [ABSTRACT FROM AUTHOR]

H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza. H5 influenza is considered a potential pandemic threat. Using deep mutational scanning, this work reveals how the >10,000 different possible amino-acid mutations in hemagglutinin affect cell entry, receptor preference, protein stability and neutralization by antibodies, which can inform real-time interpretation of viral mutations observed during surveillance of H5 influenza. [ABSTRACT FROM AUTHOR]

Introduction: Open reduction and fixation are the standard of care for treating mandibular fractures and usually lead to successful healing. However, complications such as delayed healing, non-union, and infection can compromise patient outcomes and increase healthcare costs. The initial inflammatory response, particularly the response involving specific CD8+ T cell subpopulations, is thought to play a critical role in healing long bone fractures. In this study, we investigated the role of these immune cell profiles in patients with impaired healing of mandibular fractures. Materials and methods: In this prospective study, we included patients with mandibular fractures surgically treated at Charité – Universitätsmedizin Berlin, Germany, between September 2020 and December 2022. We used follow-up imaging and clinical assessment to evaluate bone healing. In addition, we analyzed immune cell profiles using flow cytometry and quantified cytokine levels using electrochemiluminescence-based multiplex immunoassays in preoperative blood samples. Results: Out of the 55 patients enrolled, 38 met the inclusion criteria (30 men and 8 women; mean age 32.18 years). Radiographic evaluation revealed 31 cases of normal healing and 7 cases of incomplete consolidation, including 1 case of non-union. Patients with impaired healing exhibited increased levels of terminally differentiated effector memory CD8+ T cells (TEMRA) and a higher TEMRA to regulatory T cell (Treg) ratio, compared with those with normal healing. Conclusions: Our analysis of mandibular fracture cases confirms our initial hypothesis derived from long bone fracture healing: monitoring the TEMRA to Treg ratio in preoperative blood can be an early indicator of patients at risk of impaired bone healing. Radiologic follow-up enabled us to detect healing complications that might not be detected by clinical assessment only. This study highlights the potential of individual immune profiles to predict successful healing and may form the basis for future strategies to manage healing complications. [ABSTRACT FROM AUTHOR]

Background Studies have reported that repeated annual vaccination may influence influenza vaccination effectiveness in the current season. Methods We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok; Sanofi Pasteur) in adults 18–45 years of age. In the first 2 years, participants were randomized to receive vaccine or saline placebo as follows: placebo-placebo (P-P), placebo-vaccine (P-V), or vaccine-vaccine (V-V). Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of serum samples collected at 5 time points from 95 participants were tested for antibodies against vaccine strains. Results From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with smaller increases for repeat vaccinees who on average had higher prevaccination titers in year 2. There were statistically significant differences in the proportions of participants achieving ≥4-fold rises in antibody titer for the repeat vaccinees for influenza A(H1N1), B/Victoria, and B/Yamagata, but not for A(H3N2). Among participants who received vaccination in year 2, there were no significant differences between the P-V and V-V groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains. Conclusions In the first 2 years, during which influenza did not circulate, repeat and first-time vaccinees had similar postvaccination geometric mean titers to all 4 vaccine strains, indicative of similar levels of clinical protection. Clinical Trials Registration. NCT04576377 [ABSTRACT FROM AUTHOR]

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post‐marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single‐center, open‐label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre‐dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded. [ABSTRACT FROM AUTHOR]

Simon Bachler et al. present a new microfluidic platform to control the precise position and patterns of nanoliter droplets with various lipid materials. They show their platform enables monitoring of droplets and subsequent label-free mass spectrometry, which represents an important advance for the synthetic biology community.

This study examines the effects of positive compared to negative appeals in persuasive health communication about sexually transmitted diseases (STDs). The theoretical background draws on the Extended Parallel Process Model, which is mainly used to ex- plain the processing of negative appeals (fear) in these contexts. Participants (N = 160; Mage = 22.59, SD = 2.48, 57.4% female; mainly students) took part in a one-factorial experiment by viewing an advertisement promoting the use of condoms that was emotionally framed as either humorous (positive) or threatening (negative) to induce an emotional experience of joy or fear, respectively. Emotional experiences were tested as predictors for health behavior-related outcomes by means of hierarchical regression analyses. Data pro- vides evidence for the beneficial effect of positive emotional appeals on message judgment and attitudes towards the proposed behavior. The threatening appeal reduced perceptions of efficacy and led to an increase in reactance. These findings provide further evidence for carefully using fear appeals in persuasive health communication and speak in favor of integrating positive emotional appeals in these contexts.

CD4+CD25highFoxp3+ regulatory T-cells (Tregs) are functionally characterized for their ability to suppress the activation of multiple immune cell types and are indispensable for maintaining immune homeostasis and tolerance. Disruption of this intrinsic brake system assessed by loss of suppressive capacity, cell numbers, and Foxp3 expression, leads to uncontrolled immune responses and tissue damage. The conversion of Tregs to a pathogenic pro-inflammatory phenotype is widely observed in immune mediated diseases. However, the molecular mechanisms that underpin the control of Treg stability and suppressive capacity are incompletely understood. This review summarizes the concepts of Treg cell stability and Treg cell plasticity highlighting underlying mechanisms including translational and epigenetic regulators that may enable translation to new therapeutic strategies. Our enhanced understanding of molecular mechanism controlling Tregs will have important implications into immune homeostasis and therapeutic potential for the treatment of immune-mediated diseases.

Abstract Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single‐step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self‐optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two‐step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L−1 h−1 space‐time yield for this pharmaceutically relevant product.

Instant messaging (IM) is a highly diffused form of communication among younger populations, yet little is known about the emotional experience during IM. The present study aimed to investigate the emotional experience during IM by drawing on the Circumplex Model of Affect and measuring heart rate and electrodermal activity as indicators of arousal in addition to self-reported perceived emotional valence. Using an experimental design, we manipulated message latency (i.e., response after 1 min versus 7 min) and message valence (positive versus negative response). Based on data collected from 65 young adults (50% male; Mage = 23.28, SD = 3.75), we observed arousal as participants’ electrodermal activity levels increased from the time a fictitious peer started typing a response to the receipt of that response, especially in the delayed condition. Electrodermal activity levels also increased in both the positive and the negative message conditions. No changes were observed for heart rate. Participants’ self-report perceived emotional valence revealed that positive messages were evaluated as more pleasant and the peer as more available, while no difference in the self-report was found for message latency. These findings shed light on the emotional experience during IM by adding valuable insights on the physiological processes underlying the anticipation of social reward, but only during delayed IM exchange that can be observed in Human–Computer-Interaction.