Atomistic Mechanism of Lipid Membrane Binding for Blood Coagulation Factor VIII with Molecular Dynamics Simulations on a Microsecond Time Scale.

During the blood coagulation cascade, coagulation factor VIII (FVIII) is activated by thrombin to form activated factor VIII (FVIIIa). FVIIIa associates with platelet surfaces at the site of vascular damage to form an intrinsic tenase complex with activated factor IX. A working model for FVIII membrane binding involves the association of positively charged FVIII residues with negatively charged lipid headgroups and the burial of hydrophobic residues into the membrane interior.

Biophysical characterization of blood coagulation factor VIII binding to lipid nanodiscs that mimic activated platelet surfaces.

Background: Following proteolytic activation, activated blood coagulation factor (F)VIII (FVIIIa) binds to activated platelet membranes, forming the intrinsic tenase complex with activated FIX (FIXa). Previous studies have identified the C1 and C2 domains as the membrane binding domains of FVIII through conserved arginine residues. A membrane binding model for the FVIII C domains proposes that surface-exposed hydrophobic and positively charged residues at each C domain interact with the membrane, yet a comprehensive thermodynamic and structural description of this interaction is lacking.

Lifespan Extension by Retrotransposons under Conditions of Mild Stress Requires Genes Involved in tRNA Modifications and Nucleotide Metabolism.

Retrotransposons are mobile DNA elements that are more active with increasing age and exacerbate aging phenotypes in multiple species. We previously reported an unexpected extension of chronological lifespan in the yeast, , due to the presence of Ty1 retrotransposons when cells were aged under conditions of mild stress. In this study, we tested a subset of genes identified by RNA-seq to be differentially expressed in strains with a high-copy number of Ty1 retrotransposons compared with a strain with no retrotransposons and additional candidate genes for their contribution to lifespan extension when cells were exposed to a moderate dose of hydroxyurea (HU).

Blunting specific T-dependent antibody responses with engineered "decoy" B cells.

Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR-Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout "decoy" B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer.

Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor.

The development of pathogenic antibody inhibitors against coagulation factor VIII (FVIII) occurs in ∼30% of patients with congenital hemophilia A receiving FVIII replacement therapy, as well as in all cases of acquired hemophilia A. KM33 is an anti-C1 domain antibody inhibitor previously isolated from a patient with severe hemophilia A. In addition to potently blocking FVIII binding to von Willebrand factor and phospholipid surfaces, KM33 disrupts FVIII binding to lipoprotein receptor-related protein 1 (LRP1), which drives FVIII hepatic clearance and antigen presentation in dendritic cells.

Stable binding to phosphatidylserine-containing membranes requires conserved arginine residues in tandem C domains of blood coagulation factor VIII.

At sites of vascular damage, factor VIII (fVIII) is proteolytically activated by thrombin and binds to activated platelet surfaces with activated factor IX (fIXa) to form the intrinsic "tenase" complex. Previous structural and mutational studies of fVIII have identified the C1 and C2 domains in binding to negatively charged membrane surfaces through β-hairpin loops with solvent-exposed hydrophobic residues and a ring of positively charged basic residues. Several hemophilia A-associated mutations within the C domains are suggested to disrupt lipid binding, preventing formation of the intrinsic tenase complex.

A qualitative trajectory analysis of patients' experiences tapering opioids for chronic pain.

Tapering opioids for chronic pain can be challenging for both patients and prescribers, both of whom may be unsure of what to expect in terms of pain, distress, activity interference, and withdrawal symptoms over the first few weeks and months of the taper. To better prepare clinicians to provide patient-centred tapering support, the current research used prospective longitudinal qualitative methods to capture individual-level variation in patients' experience over the first few months of a voluntary physician-guided taper. The research aimed to identify patterns in individuals' experience of tapering and explore whether patient characteristics, readiness to taper, opioid tapering self-efficacy, or psychosocial context were related to tapering trajectory.

Threshold versus intensity functions in two-colour automated perimetry.

Purpose: Two-colour computerised perimetry is a technique developed for assessing cone- and rod-function at fixed background luminances in retinal disease. However, the state of adaptation during testing is unknown but crucial in the interpretation of results. We therefore aimed to determine the adaptational state of rod- and cone-mechanisms in two-colour perimetry.

Predictors of Infective Outcomes Following Hip Fracture: A Cohort Study.

This study sought to assess the value of differing pre-operative measures in prediction of post-operative non-surgical site infection (NSSI) and length of hospital stay following hip fracture surgery. All patients admitted during a one year period with a hip fracture to our department were included in the study (n=207). Primary outcome measures were ten independent risk factors correlated to the development of non-surgical site infection following surgery for hip fracture.

Retinal detachments in southern New Zealand: do poorer patients have poorer outcomes?

Aims: To investigate associations between socioeconomic status, retinal detachment type and post-operative visual outcomes in southern New Zealand. 

Methods: A retrospective review of all cases of rhegmatogenous retinal detachments in Dunedin Hospital over two years was performed. Patient demographics and macula involvement at presentation were the primary outcome measures.

The effects of long (C20/22) and short (C18) chain omega-3 fatty acids on keel bone fractures, bone biomechanics, behavior, and egg production in free-range laying hens.

Keel fractures in the laying hen are the most critical animal welfare issue facing the egg production industry, particularly with the increased use of extensive systems in response to the 2012 EU directive banning conventional battery cages. The current study is aimed at assessing the effects of 2 omega-3 (n3) enhanced diets on bone health, production endpoints, and behavior in free-range laying hens. Data was collected from 2 experiments over 2 laying cycles, each of which compared a (n3) supplemented diet with a control diet.

The changing role of the superficial region in determining the dynamic compressive properties of articular cartilage during postnatal development.

Objective: To explore how changes to the superficial region (SR) of articular cartilage during skeletal development impact its functional properties. It was hypothesised that a functional superficial region is not present in skeletally immature articular cartilage, and removal of this zone of the tissue would only negatively impact the dynamic modulus of the tissue with the attainment of skeletal maturity.

Methods: Porcine osteochondral cores were mechanically tested statically and dynamically with and without their respective superficial regions in confined and unconfined compression at different stages of postnatal development and maturation.

Postnatal changes to the mechanical properties of articular cartilage are driven by the evolution of its collagen network.

While it is well established that the composition and organisation of articular cartilage dramatically change during skeletal maturation, relatively little is known about how this impacts the mechanical properties of the tissue. In this study, digital image correlation was first used to quantify spatial deformation within mechanically compressed skeletally immature (4 and 8 week old) and mature (1 and 3 year old) porcine articular cartilage. The compressive modulus of the immature tissue was relatively homogeneous, while the stiffness of mature articular cartilage dramatically increased with depth from the articular surface.

Effects of varenicline, nicotine or placebo on depressive symptoms in postmenopausal smokers.

Background: Varenicline carries a black box warning for neuropsychiatric adverse events.

Objective: We examined varenicline use and past history of major depressive disorder (MDD) on depressive symptoms during smoking cessation.

Method: This is a secondary analysis of two smoking cessation studies in 152 postmenopausal women who received placebo or nicotine patch, or 78 women who received varenicline with relaxation.

Progression of diabetic maculopathy in patients on the Wellington Diabetic Screening Programme initially graded M3.

Aim: To determine the likelihood of progression from M3 grade maculopathy, and therefore the safety of these patients remaining under the care of a primary screener.

Methods: Patients graded M3 at diabetic screening were selected from the Wellington screening database. Photographs for this visit and the subsequent visit were obtained, and graded by a consultant ophthalmologist.

Pneumoperitoneum for neonatal laparoscopy: how safe is it?

We present the case of a 3 day old term neonate who experienced a cardiopulmonary arrest during creation of pneumoperitoneum for laparoscopic repair of duodenal atresia. The arrest was thought likely to have occurred as a result of a gas embolism. We discuss the features of the neonatal circulation which may predispose neonates to embolic phenomena during laparoscopic procedures, and the potential benefit of priming the insufflation apparatus with carbon dioxide.

Repeatability of primary selective laser trabeculoplasty in patients with primary open-angle glaucoma.

To determine if primary selective laser trabeculoplasty (SLT) can be repeated with clinical benefit in patients with primary open-angle glaucoma (POAG). Forty-two eyes of 42 patients with POAG were studied. All patients underwent primary SLT treatment of 40-50 shots to the trabecular meshwork over 360°.

The 'Dr Google' phenomenon--missed appendicitis.

Self-diagnosis has been around for many years. In today's society with free access to information, particularly through the Internet, it is more prominent than ever. With new information sources available to patients, doctors may have their diagnostic process influenced.

In vitro non-enzymatic ribation reduces post-yield strain accommodation in cortical bone.

Non-enzymatic glycation (NEG) and advanced glycation endproducts (AGEs) may contribute to bone fragility in various diseases, ageing, and other conditions by modifying bone collagen and causing degraded mechanical properties. In this study, we sought to further understand how collagen modification in an in vitro non-enzymatic ribation model leads to loss of cortical bone toughness. Previous in vitro studies using non-enzymatic ribation reported loss of ductility in the cortical bone.