Discovery of Cycloalkyl[]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold.

Commercial business and partnership aspects of general practice: the learning needs of First5 general practitioners in NHS Scotland-a qualitative study.

Objectives: To identify the learning needs of recently qualified general practitioners (GPs) (First5) in National Health Service (NHS) Scotland concerning GP partnership and the commercial business aspects of general practice. It aimed to identify learning opportunities during General Practice Specialty Training and the first 5 years of work, and to explore their suggestions of additional resources that would improve their sense of preparedness for partnership. A secondary aim was to explore what influenced their current choice of employment model and place of work.

The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C.

Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC).

Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14.

Tumor cells typically enhance their metabolic capacity to sustain their higher rate of growth and proliferation. One way to elevate the nutrient intake into cancer cells is to increase the expression of genes encoding amino acid transporters, which may represent targetable vulnerabilities. Here, we study the regulation and function of the broad amino acid transporter SLC6A14 in combination with metabolic stress, providing insights into an uncharacterized aspect of the transporter activity.

A genomic and historical synthesis of plague in 18th century Eurasia.

Plague continued to afflict Europe for more than five centuries after the Black Death. Yet, by the 17th century, the dynamics of plague had changed, leading to its slow decline in Western Europe over the subsequent 200 y, a period for which only one genome was previously available. Using a multidisciplinary approach, combining genomic and historical data, we assembled genomes from nine individuals covering four Eurasian sites and placed them into an historical context within the established phylogeny.

Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells.

Golgi stress mediates redox imbalance and ferroptosis in human cells.

Cytotoxic activities of several Golgi-dispersing compounds including AMF-26/M-COPA, brefeldin A and golgicide A have previously been shown to induce autophagy or apoptosis. Here, we demonstrate that these Golgi disruptors also trigger ferroptosis, a non-apoptotic form of cell death characterized by iron-dependent oxidative degradation of lipids. Inhibitors of ferroptosis not only counteract cell death, but they also protect from Golgi dispersal and inhibition of protein secretion in response to several Golgi stress agents.

Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported.

Monitoring long-term oral corticosteroids.

Corticosteroids are synthetic analogues of human hormones normally produced by the adrenal cortex. They have both glucocorticoid and mineralocorticoid properties. The glucocortoid components are anti-inflammatory, immunosuppressive, anti-proliferative and vasoconstrictive.

Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing.

The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin.

Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress-inducing agents.

The Golgi apparatus is part of the secretory pathway and of central importance for modification, transport and sorting of proteins and lipids. ADP-ribosylation factors, whose activation can be blocked by brefeldin A (BFA), play a major role in functioning of the Golgi network and regulation of membrane traffic and are also involved in proliferation and migration of cancer cells. Due to high cytotoxicity and poor bioavailability, BFA has not passed the preclinical stage of drug development.

Stable isotope analysis of Dacryoconarid carbonate microfossils: a new tool for Devonian oxygen and carbon isotope stratigraphy.

Rationale: Dacryoconarids are extinct marine zooplankton known from abundant, globally distributed calcite microfossils in the Devonian, but their shell stable isotope composition has not been previously explored. Devonian stable isotope stratigraphy is currently limited to less common invertebrates or bulk rock analyses of uncertain provenance. As with Cenozoic planktonic foraminifera, isotopic analysis of dacryoconarid shells could facilitate higher-resolution, geographically widespread stable isotope records of paleoenvironmental change, including marine hypoxia events, climate changes, and biocrises.

Parents of preterm-born children; sources of stress and worry and experiences with an early intervention programme - a qualitative study.

Background: Preterm-born children are at increased risk of adverse developmental outcomes, and their parents may experience increased stress levels. The Mother-Infant Transaction Program (MITP) is an early intervention that aims to enhance the parent-infant relationship and child development. The present study investigated differences in parents' experience of stress and concerns about caring for their preterm-born child according to whether they participated in the programme.

Tissue Doppler imaging in very preterm infants during the first 24 h of life: an observational study.

Background: Very preterm newborn infants often need cardiovascular support. More knowledge about myocardial function and factors that influence the immature myocardium may be helpful for optimising cardiovascular support in these infants.

Objective: Serial assessment of global myocardial function by means of colour tissue Doppler imaging (cTDI) in very and extremely preterm infants during the first 24 h of life.

Early fetal binge alcohol exposure predicts high behavioral symptom scores in 5.5-year-old children.

Background: Fetal binge alcohol exposure has been associated with neurobehavioral and cognitive symptoms. This study explored whether binge drinking mainly before recognition of pregnancy predicted high symptom scores on the Strengths and Difficulties Questionnaire (SDQ) in 5.5-year-old children.

Effect of an early intervention programme on development of moderate and late preterm infants at 36 months: a randomized controlled study.

Unlabelled: Aim of the present study was to examine the long-term effect of an early intervention for preterm infants on cognitive, gross motor and behavioural outcomes at 36 months corrected age. One hundred and eighteen preterm infants born 2005-2006 with gestational age ≥ 30.0 and <36.

Effects of a single-dose hypertonic saline hydroxyethyl starch on cerebral blood flow, long-term outcome, neurogenesis, and neuronal survival after cardiac arrest and cardiopulmonary resuscitation in rats*.

Objective: The beneficial effects of hypertonic saline on neuronal survival and on cerebral blood flow have been shown in several animal models of global and focal brain ischemia. Because of the potential benefits of hypertonic solutions, it is hypothesized that hydroxyethyl starch enhances cerebral blood flow and improves long-term outcome after cardiac arrest and cardiopulmonary resuscitation in an animal model.

Design: Laboratory animal study.

Metabolic acidosis mimicking diabetic ketoacidosis after use of calorie-free mineral water.

A previously healthy boy was admitted with fever, tachycardia, dyspnea, and was vomiting. A blood test showed a severe metabolic acidosis with pH 7.08 and an anion gap of 36 mmol/L.

Effects of early mother-infant intervention on outcomes in mothers and moderately and late preterm infants at age 1 year: a randomized controlled trial.

Objective: There is a dearth of knowledge about the effects of early interaction-based interventions on parenting and infant communication skills in moderately and late preterm infants.

Aims: Assess in a RCT the effects of the Mother-Infant Transaction program (MITP) on maternal depression and stress, breastfeeding and mothers' perception of infant temperament; and MITP's impact on preterm infant communication skills at 12 months.

Methods: Mothers/preterm infants (30-36 weeks) were randomly assigned to MITP (intervention group) or standard care (control group).