Moesgaardkristensen6493

randomised studies are required to evaluate these findings.We here describe a computational approach (POEM Pocket Oriented Elaboration of Molecules) to drive the generation of target-focused libraries while taking advantage of all publicly available structural information on protein-ligand complexes. A collection of 31 384 PDB-derived images with key shapes and pharmacophoric properties, describing fragment-bound microenvironments, is first aligned to the query target cavity by a computer vision method. The fragments of the most similar PDB subpockets are then directly positioned in the query cavity using the corresponding image transformation matrices. Lastly, suitable connectable atoms of oriented fragment pairs are linked by a deep generative model to yield fully connected molecules. POEM was applied to generate a library of 1.5 million potential cyclin-dependent kinase 8 inhibitors. By synthesizing and testing as few as 43 compounds, a few nanomolar inhibitors were quickly obtained with limited resources in just two iterative cycles.This review focuses on research my colleagues and I have conducted on etiological pathways to depression. Much of this work has focused on the measurement of neural responses to appetitive cues, using two event-related brain potential (ERP) components, the Late Positive Potential (LPP) and the Reward Positivity (RewP). Reductions in each of these components have been associated with current symptoms of depression, and in some cases have been shown to differentiate anxious from depressive phenotypes. In this review, I will describe three broad and related approaches we have taken in our research to address a series of interdependent issuess. The first attempts to understand different sources of variation in the LPP and RewP, and how these sources interact with one another. The second tries to identify whether variation in the processes measured by these ERP components might reflect a latent vulnerability to depression and its symptoms, that is evident prior to illness onset. And the third examines the possibility that the processes reflected in the LPP and RewP might play a mechanistic role in the development of depression.

The objective of this study was to analyse the preoperative medication management within the cardiac surgery patient population and measure the effectiveness of an interprofessional intervention in routine care.

A jointly developed preoperative medication management was implemented in routine care on multiple levels (inclusion in admission letter to primary care, hotline for inquiries, pocket cards for physicians and correspondence with referring centres). The effectiveness was evaluated by analysing preoperative management before and after implementation. The primary endpoint was the number of drugs managed correctly according to the guidelines after implementation. Secondary endpoints consisted amongst others of bleeding on the intensive care unit, re-thoracotomy, postoperative infarction and cerebrovascular complications. Additionally, possible associations between the correct management and different variables were investigated by multivariate analysis.

After the implementation, the number of drugs ive medication management in cardiac surgery patients. Sodium-glucose transporter-2 inhibitors, metformin and direct oral anticoagulants appear to be especially at risk for incorrect management before cardiac surgery with possible adverse events.High endothelial venule protein/SPARC-like 1 (hevin/Sparcl1) is an astrocyte-secreted protein that regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared with WT mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than WT mice from neuropathic pain after nerve injury. Intrathecal injection of WT hevin was sufficient to induce persistent mechanical allodynia in naive mice. In hevin-null mice with nerve injury, adeno-associated-virus-mediated (AAV-mediated) re-expression of hevin in glial fibrillary acidic protein-expressing (GFAP-expressing) spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin-potentiated N-Methyl-D-aspartic acid (NMDA) currents are mediated by GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing Ab against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin that was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal Ab may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS's ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.We examined the burnout status, professional satisfaction and intention to leave the profession of nurses who are actively working in Turkey during the COVID-19 pandemic period. We conducted the descriptive study with 371 nurses and collected using Copenhagen Burnout Scale (CBS), Occupational satisfaction scale (OSS) and Intention to leave the profession scale (ILPS). In this study, nurses showed a high level of exhaustion and intention to leave work, and a low level of occupational satisfaction. In the fight against COVID-19, the continuity of health services, at the same time, in order to provide adequate quality and safe health care, reducing working hours, bringing the shifts to an appropriate and reasonable time, improving the working environment and approaches that will increase their motivation and professional satisfaction are important to prevent nurses from experiencing burnout and to keep them in their professions and workplaces.

This methodological essay discusses the following question How can researchers' competences in exploring existential aspects related to healthcare be enhanced? Exploring this novel perspective on caring practice may help us better understand and communicate about experiences and issues that matter to others (e.g. patients/users). Two things are needed firstly, a vocabulary mirroring an "aesthetic-holistic" research approach allowing us to capture the essence of "what it is like" and secondly, the development of skills and competences allowing us to understand complex aspects of caring that are embodied, ethically sensitive and sustainable.

To identify personal competences and approaches underpinning research exploring "what it is like"-understanding human existence.

The discussion addresses three questions (A) What does human science exploring human existence search for? (B) Which researcher competences are required? (C) Which theoretical and practical approaches and dimensions may enhance the researche context, contemplative and creative dimensions are important to apply.

Researchers who explore humanity may benefit from cultivating awareness, sensitivity and understanding while displaying openness towards the other (the patients' or users' experiences). In this context, contemplative and creative dimensions are important to apply.BACKGROUNDA patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers.METHODSWe generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.RESULTSWe report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures.CONCLUSIONWhile we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.TRIAL REGISTRATIONNot applicable.FUNDINGThe Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Seed germination is controlled by the soil microclimate, which is expected to change with the temperature increase and rainfall irregularity predicted for the future. Because changes in soil characteristics directly affect species recruitment, vegetation dynamics and resilience, we investigated how caryopses of native grasses from dry and wet grasslands respond to water stress under current and future temperature regimes.

Caryopses were collected from 10 grass species in dry and wet grasslands, subjected or not to a fire event, and tested for germination at increasing osmotic potential (0 to -1.0 MPa) at current (17°/27°C night/day) and future (23°/33°C) simulated temperatures.

The viability and germination percentages of caryopses from both dry and wet grassland species were progressively reduced as osmotic stress increased, irrespective of temperature regime. PDD00017273 The viability of caryopses from wet grassland species was reduced under the future temperature regime, irrespective of osmotic potential. The slow germination of caryopses of dry grassland species at the present temperature regime was absent when they were incubated in the future temperature regime.