Autoreactive B cells recruited to lungs by silica exposure contribute to local autoantibody production in autoimmune-prone BXSB and B cell receptor transgenic mice.

Occupational exposure to inhaled crystalline silica dust (cSiO2) is linked to systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic autoantibody vasculitis. Each disease has a characteristic autoantibody profile used in diagnosis and implicated in pathogenesis. A role for cSiO2 in modulating humoral autoimmunity is supported by findings in mice, where respirable cSiO2 induces ectopic lymphoid structures as well as inflammation in exposed lungs across genetically diverse backgrounds.

C3d Elicits Neutrophil Degranulation and Decreases Endothelial Cell Migration, with Implications for Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d.

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population.

The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is strongly associated with COPD, even in never-smokers. Moderate AATD genotypes (MZ and SZ) have been shown to increase the severity of COPD in smokers. In this comparative study, we examine the association between AATD, genotypes, and smoking cessation.

Community nursing services during the COVID-19 pandemic: the Singapore experience.

Community nurses in Singapore support vulnerable older persons with chronic health condition(s). In the situation of scaled-down community health and social services during the COVID-19 outbreak, the community nursing team adopted measures for pandemic preparedness. This report is to share the Singapore General Hospital community nursing experience, preparation and transforming efforts during the pandemic.

Success of surgical interventions for direct dental implant-related injuries to the mandibular nerve: a review.

To the best of our knowledge there are no guidelines regarding the surgical management of dental implant-related injuries to the mandibular nerve. This review aims to investigate the success of different surgical interventions. Neurosensory injury to the mandibular branch of the trigeminal nerve can occur during administration of local anaesthetic, elevation of the flap, preparation for osteotomy, and placement of the implant.

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.

Introduction: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy.

Methods: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation.

Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice.

Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models.

The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals.

Alpha-1 antitrypsin (AAT) is the most abundant serine protease inhibitor circulating in the blood. AAT deficiency (AATD) is an autosomal codominant condition affecting an estimated 3.4 million individuals worldwide.

Myosin II sequences for Lethocerus indicus.

We present the genomic and expressed myosin II sequences from the giant waterbug, Lethocerus indicus. The intron rich gene appears relatively ancient and contains six regions of mutually exclusive exons that are alternatively spliced. Alternatively spliced regions may be involved in the asymmetric myosin dimer structure known as the interacting heads motif, as well as stabilizing the interacting heads motif within the thick filament.

Socket preservation.

Socket preservation maintains bone volume post-extraction in anticipation of an implant placement or fixed partial denture pontic site. This procedure helps compensate for the resorption of the facial bone wall. Socket preservation should be considered when implant placement needs to be delayed for patient or site-related reasons.

Brief Report: Genetic Variation of the α -Antitrypsin Gene Is Associated With Increased Autoantibody Production in Rheumatoid Arthritis.

Objective: To examine the prevalence of α -antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti-citrullinated peptide autoantibodies (ACPAs).

Methods: RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation.

Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway.

The path of least resistance in oral surgery.

Statement Of The Problem: Antibiotic resistance is an imminent threat to worldwide public health. Dental professionals must demonstrate judicious use of antibiotics and educate their patients about the risks associated with their overuse. PURPOSE OF THE PAPER: To encourage the dental profession to prescribe responsibly in order to optimise the use of antibiotics in oral surgery.

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis.

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions.

The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease.

Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland.

Effect of food service nutrition improvements on elementary school cafeteria lunch purchase patterns.

Background: Schools can play a major role in prevention and intervention for childhood obesity. We describe changes in elementary school cafeteria lunch sales patterns resulting from nutritional improvements in menu offerings that were part of a community-wide focus on health.

Methods: Elementary school lunch sales data were collected for 1 week in each of 7 years in a district serving a predominantly poor, rural, and Caucasian student population, with high rates of obesity.

Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS).

Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111.

Glutathionylation at Cys-111 induces dissociation of wild type and FALS mutant SOD1 dimers.

Mutation of the ubiquitous cytosolic enzyme Cu/Zn superoxide dismutase (SOD1) is hypothesized to cause familial amyotrophic lateral sclerosis (FALS) through structural destabilization leading to misfolding and aggregation. Considering the late onset of symptoms as well as the phenotypic variability among patients with identical SOD1 mutations, it is clear that nongenetic factor(s) impact ALS etiology and disease progression. Here we examine the effect of Cys-111 glutathionylation, a physiologically prevalent post-translational oxidative modification, on the stabilities of wild type SOD1 and two phenotypically diverse FALS mutants, A4V and I112T.

The molecular chaperone Hsp90 is required for mRNA localization in Drosophila melanogaster embryos.

Localization of maternal nanos mRNA to the posterior pole is essential for development of both the abdominal segments and primordial germ cells in the Drosophila embryo. Unlike maternal mRNAs such as bicoid and oskar that are localized by directed transport along microtubules, nanos is thought to be trapped as it swirls past the posterior pole during cytoplasmic streaming. Anchoring of nanos depends on integrity of the actin cytoskeleton and the pole plasm; other factors involved specifically in its localization have not been described to date.

Concerning the chemical nature of tubulin subunits that cap and stabilize microtubules.

There is no definitive evidence on the nature of the cap at microtubule ends that is responsible for dynamic instability behavior. It was, therefore, of interest that steady-state microtubules assembled in 20 mM P(i) buffer and pulsed for 15-60 min with [gamma-(32)P]GTP contained approximately 26 [(32)P]P(i)/microtubule [Panda et al. (2002) Biochemistry 41, 1609-1617].

Dissociation of the tubulin dimer is extremely slow, thermodynamically very unfavorable, and reversible in the absence of an energy source.

The finding that exchange of tubulin subunits between tubulin dimers (alpha-beta + alpha'beta' <--> alpha'beta + alphabeta') does not occur in the absence of protein cofactors and GTP hydrolysis conflicts with the assumption that pure tubulin dimer and monomer are in rapid equilibrium. This assumption underlies the many physical chemical measurements of the K(d) for dimer dissociation. To resolve this discrepancy we used surface plasmon resonance to determine the rate constant for dimer dissociation.

Music and the brain: the impact of music on an oboist's fight for recovery.

A 20-year-old female, alias Sara, was an aspiring professional oboist who studied music performance at college level. While wading across a river she lost her balance, was swept down river, and suffered profound injuries including severe hypothermia, cardiac arrest, and hypoxic brain injury. While recovering, her family and friends surrounded Sara with music.