Integrated Dual-Channel Retrograde Signaling Directs Stress Responses by Degrading the HAT1/TPL/IMPα-9 Suppressor Complex and Activating CAMTA3.

The intricate communication between plastids and the nucleus, shaping stress-responsive gene expression, has long intrigued researchers. This study combines genetics, biochemical analysis, cellular biology, and protein modeling to uncover how the plastidial metabolite MEcPP activates the stress-response regulatory hub known as the Rapid Stress Response Element (RSRE). Specifically, we identify the HAT1/TPL/IMPα- 9 suppressor complex, where HAT1 directly binds to RSRE and its activator, CAMTA3, masking RSRE and sequestering the activator. Stress-induced MEcPP disrupts this complex, exposing RSRE and releasing CAMTA3, while enhancing Ca 2+ influx and raising nuclear Ca 2+ levels crucial for CAMTA3 activation and the initiation of RSRE- containing gene transcription. This coordinated breakdown of the suppressor complex and activation of the activator highlights the dual-channel role of MEcPP in plastid-to- nucleus signaling. It further signifies how this metabolite transcends its expected biochemical role, emerging as a crucial initiator of harmonious signaling cascades essential for maintaining cellular homeostasis under stress. Summary: This study uncovers how the stress-induced signaling metabolite MEcPP disrupts the HAT1/TPL/IMPα-9 suppressor complex, liberating the activator CAMTA3 and enabling Ca 2+ influx essential for CAMTA3 activation, thus orchestrating stress responses via repressor degradation and activator induction.

UPLC-MS/MS method for fluconazole determination in plasma and its application in Mexican patients with candidaemia.

Aim: An accurate and fast ultra-high performance liquid chromatography coupled with tandem mass spectrometry analytical method was developed and validated for quantifying fluconazole levels in human plasma according to the US FDA guidelines.Materials & methods: A simple protein precipitation by acetonitrile was employed for the sample preparation. The chromatographic separation was carried out using isocratic elution of water (0.1% formic acid) and acetonitrile on an Acquity ultra-high performance liquid chromatography HSS T3 column. Samples from ten adult patients diagnosed with candidemia who received fluconazole treatment were analyzed.Results & conclusion: The method demonstrated excellent linearity and stability within the 1-50 µg/ml range (r2 >0.999). The intraday and interday precision were determined with coefficient of variation values ranging from 1.4 to 4.38% and 2.8 to 6.6%, respectively. This rapid and selective method has successfully analyzed 27 plasma samples. The straightforward sample preparation in a single step and the reduced analysis time make this method suitable for adult patients with candidemia, leading to improved clinical outcomes.

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Gastritis cystica profunda in a Western population without previous gastric surgery.

Gastritis cystica profunda (GCP) is a rare entity characterized by foveolar hyperplasia and cystic dilation of the gastric mucosa and submucosal glands. Its etiopathogenesis remains unknown. It has been associated with chronic inflammatory conditions, such as gastric surgery or bile reflux. The diagnosis is histological, although endoscopic ultrasound (EUS) may be useful for initial suspicion. We present a series of cases from our center, where six cases of GCP were collected between 2012 and 2022, with no history of gastric surgery. The most common locations were the antrum (50%), fundus (33%), and body (17%). Endoscopic findings included polyps ranging from 7 to 50 mm. The treatment was en bloc mucosectomy for lesions ≤20 mm and piecemeal mucosectomy for lesions >20 mm. Recurrence was observed in four patients (67%). Histologically, displaced gastric glands were found in the submucosa with cystic dilation, without dysplastic changes.

An assessment of ChatGPT's responses to frequently asked questions about cervical and breast cancer.

BACKGROUND: Cervical cancer (CC) and breast cancer (BC) threaten women's well-being, influenced by health-related stigma and a lack of reliable information, which can cause late diagnosis and early death. ChatGPT is likely to become a key source of health information, although quality concerns could also influence health-seeking behaviours. METHODS: This cross-sectional online survey compared ChatGPT's responses to five physicians specializing in mammography and five specializing in gynaecology. Twenty frequently asked questions about CC and BC were asked on 26th and 29th of April, 2023. A panel of seven experts assessed the accuracy, consistency, and relevance of ChatGPT's responses using a 7-point Likert scale. Responses were analyzed for readability, reliability, and efficiency. ChatGPT's responses were synthesized, and findings are presented as a radar chart. RESULTS: ChatGPT had an accuracy score of 7.0 (range: 6.6-7.0) for CC and BC questions, surpassing the highest-scoring physicians (P < 0.05). ChatGPT took an average of 13.6 s (range: 7.6-24.0) to answer each of the 20 questions presented. Readability was comparable to that of experts and physicians involved, but ChatGPT generated more extended responses compared to physicians. The consistency of repeated answers was 5.2 (range: 3.4-6.7). With different contexts combined, the overall ChatGPT relevance score was 6.5 (range: 4.8-7.0). Radar plot analysis indicated comparably good accuracy, efficiency, and to a certain extent, relevance. However, there were apparent inconsistencies, and the reliability and readability be considered inadequate. CONCLUSIONS: ChatGPT shows promise as an initial source of information for CC and BC. ChatGPT is also highly functional and appears to be superior to physicians, and aligns with expert consensus, although there is room for improvement in readability, reliability, and consistency. Future efforts should focus on developing advanced ChatGPT models explicitly designed to improve medical practice and for those with concerns about symptoms.

A bottom-up framework for nurses' protocol-based care decision-making.

AIM: To develop a conceptual framework for nurses' protocol-based care decision-making. DESIGN: Miles & Huberman's bottom-up approach to developing conceptual frameworks was followed, using data collected from a multiple embedded case study examining protocol-based decision-making by nurses in three hospital wards within a university hospital in northern Spain. METHODS: The qualitative data from the case study, obtained through documentary analysis, observations, and interviews, underwent a secondary analysis consisting of four steps: data reduction, data display, comparison, and drawing conclusions. RESULTS: The framework for protocol-based care decision-making comprises four components: (1) protocol-based care, as a balance between standardisation and individualised care, (2) the process, (3) the context, and (4) the elements of protocol-based care decision-making. These components and their relationship as a context-dependent, linear, variable and multifactorial process, directly influenced by the perception of risk, are described and illustrated. CONCLUSIONS: This study provides a rigorous bottom-up framework for nurses' protocol-based care decision-making. The framework could be a valuable resource for managers, clinical nurses, educators, and researchers to guide and evaluate nurses' decision-making, leading to improved care quality and reduced variability in clinical practice. Furthermore, the framework lays a foundation for further research and practical applications. IMPACT: This study addressed the problem of understanding nurses' protocol-based care decision-making and the need for a specific conceptual framework. The main findings of the study contribute to the development of a rigorous bottom-up framework comprising four components of protocol-based care decision-making. The framework has the potential to improve care quality, reduce variability, enhance patient safety, and increase healthcare efficiency by guiding nurses' decision-making in various healthcare settings. NO PATIENT OR PUBLIC CONTRIBUTION: Patient or public contribution was not applicable since the study focused on nurses' decision making.

We are MedChem: The Frontiers in Medicinal Chemistry 2024.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17th to 20th 2024 in Munich. Co-organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs-Maximilians-University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four-day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.

Combination of ß-mannanase plus multi-carbohydrase complex in simple or complex post-weaned pig diets on nutrient metabolism and gut health.

This study was conducted to evaluate whether adding ß-mannanase alone or in combination with a multi-carbohydrase complex to simple and complex diets could improve diet digestibility, nutrient and energy metabolism, and gut health in weaned pigs. Thirty pigs (7.9 kg ± 0.851 kg) weaned at 28 days were randomly split into a 2 × 3 factorial arrangement, considering a simple (corn and soybean meal-based diet) or complex diet (13% point reduction in inclusion of soybean meal, 5% of whey power, and 2.5% of spray-dried plasma compared to the simple diet) and diet without any addition (control) or the addition of ß-mannanase (BM; 0.300 g/kg of the diet) or ß-mannanase plus a multi-carbohydrase complex blend such as xylanase, ß-glucanase, and arabinofuranosidases (BM + MCC; 0.300 + 0.050 g/kg of the diet) for 17 days post-weaned. Total fecal and urine samples were collected on days 11-17. Fecal samples were collected from all pigs to identify fecal biomarkers using commercial ELISA tests. Blood samples were collected from all pigs at the end of the experimental period to assess serum concentrations of acute-phase proteins. All pigs were euthanized on day 18 for intestinal tissue collection. The simple diet had greater (p < 0.05) protein digestibility and metabolizability coefficients than the complex diet. Greater (p < 0.05) energy digestibility and energy metabolizability coefficients were observed in the BM and BM+ MCC compared to the control diet. On average, BM improved by 64 kcal/kg and BM + MCC improved by 100 kcal/kg of metabolizable energy. Furthermore, the addition of BM and BM + MCC to the diets led to lower fecal moisture and fecal output. Moreover, the BM and BM + MCC diets also reduced fecal calprotectin concentrations by 29 and 46%, respectively, compared to control pigs (p < 0.001). We conclude that simple diets are a suitable alternative to complex diets, without compromising the nutrient digestibility and gut health of post-weaned pigs. The addition of exogenous enzymes improves nutrient and energy utilization, as well as the absorption area, and decreases calprotectin concentrations.

Evaluation of Unsaponifiable Fraction of Avocado Oil on Liver and Kidney Mitochondrial Function in Rats Fed a High-Fat and High-Carbohydrate Diet.

High-fat and high-carbohydrate (HF-HC) diets induce metabolic syndrome via mitochondrial dysfunction and oxidative stress. We have previously shown that this may be prevented by avocado oil, a source of bioactive molecules with antioxidant properties. However, it is unknown if these effects are mediated by the unsaponifiable fraction of avocado oil (UFAO). Thus, we tested if this fraction improves glucose metabolism, bioenergetics and oxidative stress in mitochondria from the kidney and liver of rats fed an HF-HC diet. We found that 12 weeks of an HF-HC diet impaired glucose utilization and increased insulin resistance, which was prevented by UFAO administration. The HF-HC diet decreased respiration, membrane potential and electron transport chain (ETC) function in liver and kidney mitochondria. These mitochondrial dysfunctions were prevented by UFAO intake. Unexpectedly, UFAO increased ROS levels in the mitochondria of control animals and did not decrease them in rats with an HF-HC diet; however, UFAO protects liver and kidney mitochondria from iron-induced oxidative stress. These findings suggest that impairments in glucose metabolism and mitochondrial function by an HF-HC diet may be prevented by UFAO, without decreasing ROS generation but protecting mitochondria from oxidative damage.

Lipid Quality Changes in French Fries, Chicken Croquettes, and Chicken Nuggets Fried with High-Linoleic and High-Oleic Sunflower Oils in Domestic Deep Fryers.

The quality of fried products greatly depends on the changes occurring during frying. The purpose of this work was to study the lipid quality changes taking place in selected frozen foods after domestic deep-frying. Conventional, high-linoleic sunflower oil (HLSO) and high-oleic sunflower oil (HOSO) were used, and the frozen foods selected were French fries, croquettes, and nuggets. The foods were fried in domestic fryers under discontinuous conditions. Analyses included fatty acid composition, sterols, tocopherols, squalene, and lipid alteration levels. In all fried foods, the content of lipids increased after frying, which is consistent with previous findings. However, the lipid exchange between the food and the oil greatly depended on the food characteristics. Specifically, the levels of frying oil in the food lipids were about 90, 40, and 58% for French fries, croquettes, and nuggets, respectively. The main results obtained showed that lipid alteration levels considerably decreased and amounts of sterols and tocopherols significantly increased in French fries' lipids after frying. In both chicken products, croquettes and nuggets, the best quality improvement observed was a significant decrease in cholesterol in food lipids due to the lipid exchange. Overall, frying with HLSO and HOSO improved the quality and nutritional properties of all products tested.

Behavior, Intake, Digestion and Milk Yield of Early Lactation Holstein Dairy Cows with Two Levels of Environmental Exposure and Feeding Strategy.

Eighty-four autumn (ACS, n = 45)- and spring (SCS, n = 39)-calved multiparous early lactation Holstein cows were assigned to groups of either: (a) grazing + mixed ration (MR) during partial confinement in outdoor soil-bedded pens with shade (OD-GRZ); (b) grazing + MR during partial confinement in a compost-bedded pack barn with cooling (CB-GRZ); or (c) total confinement fed a totally mixed ration (CB-TMR) in a compost-bedded pack barn. Data were analyzed using the SAS MIXED procedure with significance at p ≤ 0.05. In both seasons, despite behavioral differences (p < 0.05) between the OD-GRZ and CB-GRZ groups (i.e., standing, first grazing meal length, bite rate), the milk and component yields, DM intake, microbial CP output (MCP) and NE efficiency were unaffected by the housing conditions, possibly due to mild weather conditions. The milk yield was substantially higher in the CB-TMR group versus the OD-TMR and CB-TMR groups (p < 0.01) in both ACS (~35%) and SCS (~20%) despite there being no intake differences, without any impact on milk component levels. In ACS, this was associated with a higher MCP, likely due to the higher nutritional value of TMR compared to pasture, which was not the case in SCS. In conclusion, the OD-GRZ group achieved the same milk production as the CB-GRZ group through behavior adaptation, under mild weather conditions, in both calving seasons. The CB-TMR group outperformed the grazing systems in both calving seasons, regardless of the MCP.

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

Development of the Home Environmental Scale of Accessibility Instrument for Spain.

BACKGROUND: Universal accessibility is one of the most active lines of intervention for people with disabilities and older adults. This accessibility has become a topic of growing interest regarding home access and use. Therefore, the main objective of this study was to create and validate a home assessment tool: the HESA II. METHODS: The study was conducted in four phases: (1) agreement on variables by an expert panel; (2) development of 90 items according to the AOTA framework; (3) pilot test with n = 20; and (4) final study with 156 subjects where confirmatory factor analysis was performed. RESULTS: The tool consisted of 85 items divided into five subscales related to each of the main spaces of Spanish homes: living room; kitchen; bedroom; and bathroom. CONCLUSIONS: The tool demonstrates good psychometric properties of reliability. The HESA II assesses home accessibility based on limitations in activity and participation restriction of the evaluated person as per the International Classification of Functioning, Disability, and Health rather than on a diagnosis, making it applicable to a wide range of groups.

Increasing ventilation in drowning resuscitation - A cross-over randomized simulation study of ventilation during automated external defibrillator analysis pauses.

Objective: The aim of this study was to analyze the feasibility of a new resuscitation strategy in which breaths are provided during automated external defibrillator (AED) rhythm analysis, and to evaluate its impact on chest compressions (CC) quality and the peri-analysis time. Method: A randomized simulation study, comparing two cardiopulmonary resuscitations strategies, has been conducted: the standard strategy (S1) with strategy involving ventilation during AED analysis (S2). Thirty lifeguards have performed both strategies in a cross-over study design during 10 min of CPR. Results: The number of ventilations per 10 min increases from 47 (S1) to 72 (S2) (p < 0.001). This results in the delivery of an additional 17.1 L of insufflated air in S2 compared to S1 (p < 0.001). There have been no significant changes in frequency and total number of CC. These findings correspond to a reduction of the non-ventilation period from 176 s (S1) to 48 s (S2). Conclusions: This simulation study suggests that it is feasible to increase the number of ventilations during resuscitation following drowning, without affecting the quantity and quality of chest compressions. The results of this study may serve as a foundation for further investigation into optimal ventilation strategies in this context.

Taboo language across the globe: A multi-lab study.

The use of taboo words represents one of the most common and arguably universal linguistic behaviors, fulfilling a wide range of psychological and social functions. However, in the scientific literature, taboo language is poorly characterized, and how it is realized in different languages and populations remains largely unexplored. Here we provide a database of taboo words, collected from different linguistic communities (Study 1, N = 1046), along with their speaker-centered semantic characterization (Study 2, N = 455 for each of six rating dimensions), covering 13 languages and 17 countries from all five permanently inhabited continents. Our results show that, in all languages, taboo words are mainly characterized by extremely low valence and high arousal, and very low written frequency. However, a significant amount of cross-country variability in words' tabooness and offensiveness proves the importance of community-specific sociocultural knowledge in the study of taboo language.

Plant U-Box 4 regulates chloroplast stress signaling and programmed cell death via Salicylic acid modulation.

In response to environmental stress, chloroplasts generate reactive oxygen species, including singlet oxygen (1O2), which regulates nuclear gene expression (retrograde signaling), chloroplast turnover, and programmed cell death (PCD). Yet, the central signaling mechanisms and downstream responses remain poorly understood. The Arabidopsis thaliana plastid ferrochelatase two (fc2) mutant conditionally accumulates 1O2 and involves Plant U-Box 4 (PUB4), a cytoplasmic E3 ubiquitin ligase, in propagating these signals. To gain insights into 1O2 signaling pathways, we compared transcriptomes of fc2 and fc2 pub4 mutants. The accumulation of 1O2 in fc2 plants broadly repressed genes involved in chloroplast function and photosynthesis, while 1O2 induced genes and transcription factors involved in abiotic and biotic stress, the biosynthesis of jasmonic acid (JA), and Salicylic acid (SA). Elevated JA and SA levels were observed in stressed fc2 plants, but were not responsible for PCD. pub4 reversed the majority of 1O2-induced gene expression in fc2 and reduced the JA content, but maintained elevated levels of SA even in the absence of 1O2 stress. Reducing SA levels in fc2 pub4 restored 1O2 signaling and light sensitivity. Together, this work demonstrates that SA plays a protective role during photo-oxidative stress and that PUB4 mediates 1O2 signaling by modulating its levels.

Activation of stress-response genes by retrograde signaling-mediated destabilization of nuclear importin IMPα-9 and its interactor TPR2.

Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists. To address this, we performed a suppressor screen of the ceh1 mutant, which contains elevated 2-C-methyl-d-erythritol-2,4-cyclopyrophosphate (MEcPP) levels, and identified the gain-of-function mutant impα-9, which shows reversed dwarfism and suppressed expression of stress-response genes in the ceh1 background despite heightened MEcPP. Subsequent genetic and biochemical analyses established that the accumulation of MEcPP initiates an upsurge in Arabidopsis SKP1-like 1 (ASK1) abundance, a pivotal component in the proteasome degradation pathway. This increase in ASK1 prompts the degradation of IMPα-9. Moreover, we uncovered a protein-protein interaction between IMPα-9 and TPR2, a transcriptional co-suppressor and found that a reduction in IMPα-9 levels coincides with a decrease in TPR2 abundance. Significantly, the interaction between IMPα-9 and TPR2 was disrupted in impα-9 mutants, highlighting the critical role of a single amino acid alteration in maintaining their association. Disruption of their interaction results in the reversal of MEcPP-associated phenotypes. Chromatin immunoprecipitation coupled with sequencing analyses revealed that TPR2 binds globally to stress-response genes and suggested that IMPα-9 associates with the chromatin. They function together to suppress the expression of stress-response genes under normal conditions, but this suppression is alleviated in response to stress through the degradation of the suppressing machinery. The biological relevance of our discoveries was validated under high light stress, marked by MEcPP accumulation, elevated ASK1 levels, IMPα-9 degredation, reduced TPR2 abundance, and subsequent activation of a network of stress-response genes. In summary, our study collectively unveils fresh insights into plant adaptive mechanisms, highlighting intricate interactions among retrograde signaling, the proteasome, and nuclear transport machinery.

Correction: Influence of the carbazole moiety in self-assembling molecules as selective contacts in perovskite solar cells: interfacial charge transfer kinetics and solar-to-energy efficiency effects.

[This corrects the article DOI: 10.1039/D3NA00811H.].

Electrochemical Synthesis of a Sitagliptin Precursor.

A novel synthesis of sitagliptin based on a redox-active ester derived from the chiral pool is reported. The key step is an electrochemical nickel-catalyzed sp2-sp3 cross-coupling reaction using inexpensive nickel foam in an undivided cell. It was successfully applied to 21 examples in up to 88% yield. These sitagliptin-analogue precursors could potentially interact with the DPP4 enzyme. A full synthesis based on our new reaction pathway provided sitagliptin in an overall yield of 33%.

Takotsubo cardiomyopathy as the primary manifestation of decompensated Graves' disease.

Takotsubo cardiomyopathy (TCM) is characterized by transient left ventricular dysfunction with apical ballooning, usually observed in postmenopausal women after a stressful event. We discuss a rare presentation of TCM induced by thyrotoxicosis secondary to Graves' disease. This case raises interesting questions about the pathogenesis, diagnosis, and management of TCM. Learning objectives: 1. To recognize hyperthyroidism as a possible etiology of takutsubo cardiomyopathy.2. To identify the effect of radioiodine contrast on diagnosis of some types of takutsubo cardiomyopathy.