Dilutional control of prothrombin activation at physiologically relevant shear rates.

The generation of proteolyzed prothrombin species by preassembled prothrombinase in phospholipid-coated glass capillaries was studied at physiologic shear rates (100-1000 s(-1)). The concentration of active thrombin species (α-thrombin and meizothrombin) reaches a steady state, which varies inversely with shear rate. When corrected for shear rate, steady-state levels of active thrombin species exhibit no variation and a Michaelis-Menten analysis reveals that chemistry of this reaction is invariant between open and closed systems; collectively, these data imply that variations with shear rate arise from dilutional effects.

Prothrombin activation on the activated platelet surface optimizes expression of procoagulant activity.

Effective hemostasis relies on the timely formation of α-thrombin via prothrombinase, a Ca(2+)-dependent complex of factors Va and Xa assembled on the activated platelet surface, which cleaves prothrombin at Arg271 and Arg320. Whereas initial cleavage at Arg271 generates the inactive intermediate prethrombin-2, initial cleavage at Arg320 generates the enzymatically active intermediate meizothrombin. To determine which of these intermediates is formed when prothrombin is processed on the activated platelet surface, the cleavage of prothrombin, and prothrombin mutants lacking either one of the cleavage sites, was monitored on the surface of either thrombin- or collagen-activated platelets.

Neuronal calcium sensor proteins: emerging roles in membrane traffic and synaptic plasticity.

Ca(2+) plays a crucial role in the regulation of neuronal function. Recent work has revealed important functions for two families of neuronally expressed Ca(2+) sensor proteins. These include roles in membrane traffic and in alterations in synaptic plasticity underlying changes in behaviour.

Therapeutic targeting of respiratory syncytial virus G-protein.

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in infants and young children and an important pathogen of the elderly and immune suppressed. The only intervention currently available is a monoclonal antibody against the RSV fusion protein, which has shown utility as a prophylactic for high-risk premature infants, but which has not shown postinfection therapeutic efficacy in the specific RSV-infected populations studied. Thus, for the major susceptible populations, there remains a great need for effective treatment.

Child welfare agency ties to providers and schools and substance abuse treatment use by adolescents.

Policy makers and advocates are increasingly encouraging child-serving organizations to work together. This study examined how child welfare agency ties with substance abuse treatment providers and schools correlated with substance abuse treatment for adolescents receiving child protective services. A sample of adolescents with substance use risk was extracted from a national survey of families engaged with child welfare.

Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.

Rationale: Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis.

Decoding glutamate receptor activation by the Ca2+ sensor protein hippocalcin in rat hippocampal neurons.

Hippocalcin is a Ca(2+)-binding protein that belongs to a family of neuronal Ca(2+)sensors and is a key mediator of many cellular functions including synaptic plasticity and learning. However, the molecular mechanisms involved in hippocalcin signalling remain illusive. Here we studied whether glutamate receptor activation induced by locally applied or synaptically released glutamate can be decoded by hippocalcin translocation.

The diversity of calcium sensor proteins in the regulation of neuronal function.

Calcium signaling in neurons as in other cell types mediates changes in gene expression, cell growth, development, survival, and cell death. However, neuronal Ca(2+) signaling processes have become adapted to modulate the function of other important pathways including axon outgrowth and changes in synaptic strength. Ca(2+) plays a key role as the trigger for fast neurotransmitter release.

Prophylactic treatment with a G glycoprotein monoclonal antibody reduces pulmonary inflammation in respiratory syncytial virus (RSV)-challenged naive and formalin-inactivated RSV-immunized BALB/c mice.

We examined whether prophylactically administered anti-respiratory syncytial virus (anti-RSV) G monoclonal antibody (MAb) would decrease the pulmonary inflammation associated with primary RSV infection and formalin-inactivated RSV (FI-RSV)-enhanced disease in mice. MAb 131-2G administration 1 day prior to primary infection reduced the pulmonary inflammatory response and the level of RSV replication. Further, intact or F(ab')(2) forms of MAb 131-2G administered 1 day prior to infection in FI-RSV-vaccinated mice reduced enhanced inflammation and disease.

Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.

Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism.

Nutrition for children with epidermolysis bullosa.

Optimization of resistance to infection, growth, sexual maturation, wound healing, and provision of the best possible overall quality of life are important management goals in children with epidermolysis bullosa. However, all these goals rely on the maintenance of optimal nutritional status, and achieving this is extremely challenging in the severe types of the disease. Strategies to improve nutritional status have the best chance of success when the dietitian or nutritionist works as an integral member of the multidisciplinary team and is well informed of patients' situations, family dynamics, and prognoses.

Bioinformatic analysis of CaBP/calneuron proteins reveals a family of highly conserved vertebrate Ca2+-binding proteins.

Background: Ca2+-binding proteins are important for the transduction of Ca2+ signals into physiological outcomes. As in calmodulin many of the Ca2+-binding proteins bind Ca2+ through EF-hand motifs. Amongst the large number of EF-hand containing Ca2+-binding proteins are a subfamily expressed in neurons and retinal photoreceptors known as the CaBPs and the related calneuron proteins.

Reflux-induced collagen type v sensitization: potential mediator of bronchiolitis obliterans syndrome.

Background: Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process.

Workshop on immunizations in older adults: identifying future research agendas.

Goals for immunization in older adults may differ from those in young adults and children, in whom complete prevention of disease is the objective. Often, reduced hospitalization and death but also averting exacerbation of underlying chronic illness, functional decline, and frailty are important goals in the older age group. Because of the effect of age on dendritic cell function, T cell-mediated immune suppression, reduced proliferative capacity of T cells, and other immune responses, the efficacy of vaccines often wanes with advanced age.

Vaccination to induce antibodies blocking the CX3C-CX3CR1 interaction of respiratory syncytial virus G protein reduces pulmonary inflammation and virus replication in mice.

Respiratory syncytial virus (RSV) infection causes substantial morbidity and some deaths in the young and elderly worldwide. There is no safe and effective vaccine available, although it is possible to reduce the hospitalization rate for high-risk children by anti-RSV antibody prophylaxis. RSV has been shown to modify the immune response to infection, a feature linked in part to RSV G protein CX3C chemokine mimicry.

Antibody-mediated synergy and interference in the neutralization of SARS-CoV at an epitope cluster on the spike protein.

Incomplete neutralization of virus, especially when it occurs in the presence of excess neutralizing antibody, represents a biological phenomenon that impacts greatly on antibody-mediated immune prophylaxis of viral infection and on successful vaccine design. To understand the mechanism by which a virus escapes from antibody-mediated neutralization, we have investigated the interactions of non-neutralizing and neutralizing antibodies at an epitope cluster on the spike protein of severe acute respiratory syndrome coronavirus (SARS-CoV). The epitope cluster was mapped at the C-terminus of the spike protein; it consists of structurally intertwined epitopes recognized by two neutralizing monoclonal antibodies (mAbs), 341C and 540C, and a non-neutralizing mAb, 240C.

Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry.

Ca2+ entry through store-operated Ca2+ channels involves the interaction at ER-PM (endoplasmic reticulum-plasma membrane) junctions of STIM (stromal interaction molecule) and Orai. STIM proteins are sensors of the luminal ER Ca2+ concentration and, following depletion of ER Ca2+, they oligomerize and translocate to ER-PM junctions where they form STIM puncta. Direct binding to Orai proteins activates their Ca2+ channel function.