siRNA Features-Automated Machine Learning of 3D Molecular Fingerprints and Structures for Therapeutic Off-Target Data.

Chemical modifications are the standard for small interfering RNAs (siRNAs) in therapeutic applications, but predicting their off-target effects remains a significant challenge. Current approaches often rely on sequence-based encodings, which fail to fully capture the structural and protein-RNA interaction details critical for off-target prediction. In this study, we developed a framework to generate reproducible structure-based chemical features, incorporating both molecular fingerprints and computationally derived siRNA-hAgo2 complex structures.

Lipid-lowering therapy (LLT) in 1,100 cardiac rehabilitation patients with coronary heart disease: the LLT-R(ehabilitation) registry.

Background: Cardiac rehabilitation (CR) improves quality of life and prognosis in patients with coronary heart disease (CHD). The aim of the study was to evaluate effects of lipid-lowering therapy (LLT) in patients with CHD during and after CR.

Methods: Data from prospective, multicenter registry including 1,100 patients with CHD undergoing CR in 6 German cardiac rehabilitation centers between 2016 and 2018 were analyzed.

Circulating and hepatic levels of growth differentiation factor 15 in patients with metabolic dysfunction-associated steatotic liver disease.

Aim: Increased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow-up (n = 276).

Methods: Participants were evaluated clinically and histologically in both cohorts.

Apolipoprotein A-IV is induced by high-fat diets and mediates positive effects on glucose and lipid metabolism.

Objective: Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in circulation after six weeks of consuming a high-fat diet in humans. However, the impact of dietary changes in regulating apoA-IV, and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established.

Intraoperative Intermittent Pneumatic Compression Reduces Incidence of Venous Thromboembolism in Patients Undergoing Craniotomy: Study Protocol of a Randomized Multicenter, Single-Blind Trial.

Background And Objective: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in craniotomy patients. The duration of surgery has been identified as a risk factor for the development of VTE. In a pilot study, the use of intermittent pneumatic venous compression (IPC) dramatically reduced the incidence of VTE.

Mental computational processes have always been an integral part of motivation science.

Some constructs in motivation science are certainly underdeveloped and some motivation researchers may work with underspecified constructs, as suggested by Murayama and Jach (M&J). However, this is not indicative of a general problem in motivation science. Many motivation theories focus on specific mechanisms underlying motivated behavior and thus have already adopted the computational process perspective that M&J call for.

Amide Internucleoside Linkages Suppress the MicroRNA-like Off-Target Activity of Short Interfering RNA.

RNA interference (RNAi) has rapidly matured as a novel therapeutic approach. In this field, chemical modifications have been critical to the clinical success of short interfering RNAs (siRNAs). Notwithstanding the significant advances, achieving robust durability and gene silencing in extrahepatic tissues, as well as reducing off-target effects of siRNA, are areas where chemical modifications can still improve siRNA performance.

African Swine Fever in Saxony-Disease Dynamics.

African swine fever (ASF) emerged in Germany in 2020. A few weeks after the initial occurrence, infected wild boar were detected in Saxony. In this study, data from wild boar surveillance in Saxony were analyzed.

Incorporating Virtual Reality Agents During a Dichotic Speech Reception Task: Insights From the Heart.

Objectives: Listening effort is moderated by not only task difficulty, but also success importance. In real communication scenarios, success importance varies based upon the social context. However, in the laboratory, it can be challenging to manipulate social context without compromising experimental control.

GDF15 is still a mystery hormone.

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. Despite its identification over 20 years ago, the functions of GDF15 remain complex and not fully elucidated. Its concentration in plasma varies widely depending on the physiological and pathophysiological state of the organism.

Tranexamic Acid for reduction of intra- and postoperative TRansfusion requirements in elective Abdominal surgery (TATRA): study protocol for an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized superiority trial with two parallel groups.

Background: Intra- and postoperative hemorrhage is a relevant problem in major abdominal surgery, leading to acute anemia and necessitating transfusion of packed red blood cells. It is estimated that in 30% of abdominal surgeries, intra- or postoperative transfusion is required. Transfusion potentially has detrimental health effects and poses a considerable socioeconomic burden.

Theories and hypotheses: The forgotten plane of the multiverse.

Multiverse analyses-the systematic examination of the effects of decisions that researchers can take over the course of a research project-became more common in recent psychophysiological research. However, multiverse analyses in psychophysiology almost exclusively focus on methodological and statistical decisions that can have a considerable impact on the findings. The role of the conceptual multiverse regarding theory-related research decisions is largely ignored.

Hepatic steatosis and not type 2 diabetes, body mass index, or hepatic fibrosis associates with hyperglucagonemia in individuals with steatotic liver disease.

Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and are considered a diabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of resistance toward glucagon's effects on amino acid metabolism, resulting in an amino acid-induced hyperglucagonemia. We investigated the presence of hyperglucagonemia in individuals with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD), and whether body mass index (BMI), T2D, hepatic steatosis, and/or fibrosis contribute to this relationship.

Glucagon Resistance in Individuals With Obesity and Hepatic Steatosis Can Be Measured Using the GLUSENTIC Test and Index.

Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated.

The impact of short-term eucaloric low- and high-carbohydrate diets on liver triacylglycerol content in males with overweight and obesity: a randomized crossover study.

Background: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions.

Objectives: We hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism.

Synthesis and Properties of RNA Modified with Thioamide Internucleoside Linkage.

Recent success of RNA therapeutics has reinvigorated interest in chemical modifications of RNA. As exemplified by the phosphorothioates, modifications of sugar-phosphate backbone have been remarkably impactful but relatively underexplored in therapeutic RNAs. The present study reports synthesis, thermal stability, and RNA interference activity of RNAs modified with thioamide linkages.

Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.

Introduction: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases.

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin.

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance.

Combining Cardiovascular and Pupil Features Using k-Nearest Neighbor Classifiers to Assess Task Demand, Social Context, and Sentence Accuracy During Listening.

In daily life, both acoustic factors and social context can affect listening effort investment. In laboratory settings, information about listening effort has been deduced from pupil and cardiovascular responses independently. The extent to which these measures can jointly predict listening-related factors is unknown.

Construction of the Views oN Infant Sleep (VNIS) Questionnaire.

Parents' beliefs about infant sleep behaviour vary over time and across cultures. No validated instrument exists to understand parents' pre- and postnatal views on infant sleep behaviours, which may influence their caregiving decisions. The Views oN Infant Sleep Questionnaire (VNIS) will be a tool to assess parents' beliefs in order to facilitate tailored perinatal care, increase the reliability of postnatal self-report measures, allow for cross-cultural comparisons, and provide a baseline for researchers to use in longitudinal studies.

Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.

Background: Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake.

Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes.

Context: Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are increased in type 2 diabetes and are potential regulators of metabolism. The effect of changes in caloric intake and macronutrient composition on their circulating levels in patients with type 2 diabetes are unknown.

Objective: To explore the effects of a carbohydrate-reduced high-protein diet with and without a clinically significant weight loss on circulating levels of FGF21 and GDF15 in patients with type 2 diabetes.

Synthesis and Properties of RNA Modified with Cationic Amine Internucleoside Linkage.

Chemical modifications of RNA are important tools for the development of RNA therapeutics. The present study reports a novel RNA backbone modification that replaces the negatively charged phosphate with a positively charged amine linkage. Despite being thermally destabilizing in RNA duplexes, the amine linkage caused a relatively modest decrease of activity of a modified short interfering RNA (siRNA).