PDX1^LOW MAFA^LOW β-cells contribute to islet function and insulin release

Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Calamus caesius (Rattan) wood: Chemical constituents, biological activities’ relative medicinal properties from Thai medicinal scriptures, and in silico antioxidant activity

Calamus caesius is known as Rattan. It was found as a component of many formulas from evidence-based Thai medicinal scriptures but no research about their medicinal properties. We investigated the literature review analysis from Thai medicinal textbooks for proposed biological activity relatives including antioxidant, cytotoxic, anti-inflammatory, and antimicrobial activities, and chemical profiles using gas chromatography-mass spectrometry (GC–MS). In silico studies were inspected on tyrosinase and NAD(P)H oxidase actions. Thirty formulas from Thai medicinal textbooks found C. caesius as a component with a percent ratio in the range of 1.43 to 14.99, the formula's properties are antipyretic, followed by antidiarrhea, and cure abscesses related to inflammation and infection. Both water extracted and ethanol extracted showed high antioxidant activities in all assays and showed no toxicity in macrophage-like cells and cancer cell lines. The ethanol extracted showed slightly bactericidal better than the water extracted, none of them inhibited against C. albicans. From GC–MS analysis, the highest components of water and ethanol extract are 3-tert-Butylamino-acrylonitrile and β-Sitosterol, respectively. Five chemical compounds revealed in both water and ethanol extracted of C. caesius are 1,3-di-tert-butylbenzene; 2,6-dimethoxyphenol; 2-propylphenol; 2,4-di-tert-butylphenol; methyl palmitate. Sterol compounds such as stigmasterol, beta-sitosterol, and campesterol from ethanol extracted showed outstanding interaction with both tyrosinase and NADPH oxidase in silico molecular docking study. All outcomes proven that C. caesius has potentially antioxidant effects to support health problems. Additionally, this is the first report on the scientific data of Calamus caesius wood related to its medicinal properties in the formula from Thai medicinal scriptures

Uncovering the mechanisms of MuRF1-induced ubiquitylation and revealing similarities with MuRF2 and MuRF3

MuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene) type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with a UBE2 (ubiquitin conjugating enzyme). Our understanding of MuRF1 function remains unclear as candidate UBE2s have not been fully elucidated. In the present study, we screened human ubiquitin dependent UBE2s in vitro and found that MuRF1 engages in ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. MuRF1 can cause mono-ubiquitylation, K48- and K63-linked polyubiquitin chains in a UBE2 dependent manner. Moreover, we identified a two-step UBE2 dependent mechanism whereby MuRF1 is monoubiquitylated by UBE2W which acts as an anchor for UBE2N/V to generate polyubiquitin chains. With the in vitro ubiquitylation assay, we also found that MuRF2 and MuRF3 not only share the same UBE2 partners as MuRF1 but can also directly ubiquitylate the same substrates: Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). In summary, our work presents new insights into the mechanisms that underpin MuRF1 activity and reveals overlap in MuRF-induced ubiquitylation which could explain their partial redundancy in vivo

Towards sustainable land use: identifying and managing the conflicts between human activities and biodiversity conservation in Europe

Conflicts between biodiversity conservation and human activities are becoming increasingly apparent in all European landscapes. The intensification of agricultural and silvicultural practices, land abandonment and other land uses such as recreation and hunting are all potential threats to biodiversity that can lead to conflicts between stakeholder livelihoods and biodiversity conservation. To address the global decline in biodiversity there is, therefore, a need to identify the drivers responsible for conflicts between human activities and the conservation of European biodiversity and to promote the management of these conflicts. Here, the drivers of biodiversity conflicts are analysed in a European context for five habitat types: agricultural landscapes, forests, grasslands, uplands and freshwater habitats. A multi- disciplinary approach to conflict management is described, with active stakeholder involvement at every stage of conflict identification and management as well as a range of other approaches including stakeholder dialogue and education, consumer education, improvement of political and legislative frameworks, financial incentives, and planning infrastructur