Subfamily specific conservation profiles for proteins based on n-gram patterns

<p>Abstract</p> <p>Background</p> <p>A new algorithm has been developed for generating conservation profiles that reflect the evolutionary history of the subfamily associated with a query sequence. It is based on n-gram patterns (NP{<it>n,m</it>}) which are sets of <it>n </it>residues and <it>m </it>wildcards in windows of size <it>n+m</it>. The generation of conservation profiles is treated as a signal-to-noise problem where the signal is the count of n-gram patterns in target sequences that are similar to the query sequence and the noise is the count over all target sequences. The signal is differentiated from the noise by applying singular value decomposition to sets of target sequences rank ordered by similarity with respect to the query.</p> <p>Results</p> <p>The new algorithm was used to construct 4,248 profiles from 120 randomly selected Pfam-A families. These were compared to profiles generated from multiple alignments using the consensus approach. The two profiles were similar whenever the subfamily associated with the query sequence was well represented in the multiple alignment. It was possible to construct subfamily specific conservation profiles using the new algorithm for subfamilies with as few as five members. The speed of the new algorithm was comparable to the multiple alignment approach.</p> <p>Conclusion</p> <p>Subfamily specific conservation profiles can be generated by the new algorithm without aprioi knowledge of family relationships or domain architecture. This is useful when the subfamily contains multiple domains with different levels of representation in protein databases. It may also be applicable when the subfamily sample size is too small for the multiple alignment approach.</p

Mid-term results of the Latitude primary total elbow arthroplasty

Background: The Latitude total elbow prosthesis is a third-generation implant, developed to restore the natural anatomy of the elbow. Literature on this prosthesis is scarce. The aim of this study was to analyze the mid-term results of the Latitude total elbow prosthesis. Methods: We retrospectively evaluated 62 patients (21 men and 41 women). The mean age at the time of surgery was 65 years (range, 28-87 years). The main indication for surgery was inflammatory arthritis. The outcome measures were complications, reoperations, self-reported physical functioning, pain, satisfaction, objectively measured physical functioning, and radiologic signs of loosening. Kaplan-Meier survival analysis was used to determine survival with revision as the endpoint. Results: Sixty-nine primary Latitude prostheses were placed in 62 patients between 2008 and 2019. Six patients (7 prostheses) died, 3 elbows underwent revision, and 9 patients were lost to follow-up. A total of 44 patients (50 prostheses) were available for follow-up. The mean length of follow-up was 51 months (range, 10-144 months). Kaplan-Meier survival analysis showed a survival rate of 82% at 10 years after surgery. The main reason for revision was aseptic loosening. Radial head dissociation was seen in 8 patients (24%), but none had complaints. Self-reported and objectively measured physical functioning yielded good results, although 23 patients (46%) did show radiolucent lines on radiographs. Conclusion: Latitude total elbow arthroplasty is considered a successful procedure with low pain scores, high patient satisfaction, and good physical functioning. Survival rates nonetheless remain low and complication rates remain high yet are comparable to those of other elbow arthroplasties. We recommend biomechanical studies to concentrate on specific postoperative loading instructions to minimize wear and consequent loosening

Developing a Model to Simulate the Effect of Hypothermia on Cerebral Blood Flow and Metabolism

Hypoxic ischemic encephalopathy (HIE) is a significant cause of death and neurological disability in newborns. Therapeutic hypothermia at 33.5 °C is one of the most common treatments in HIE and generally improves outcome; however 45-55% of injuries still result in death or severe neurodevelopmental disability. We have developed a systems biology model of cerebral oxygen transport and metabolism to model the impact of hypothermia on the piglet brain (the neonatal preclinical animal model) tissue physiology. This computational model is an extension of the BrainSignals model of the adult brain. The model predicts that during hypothermia there is a 5.1% decrease in cerebral metabolism, 1.1% decrease in blood flow and 2.3% increase in cerebral tissue oxygenation saturation. The model can be used to simulate effects of hypothermia on the brain and to help interpret bedside recordings

Melanoma incidence and mortality in Scotland 1979–2003

We studied 12 450 cases of invasive melanoma diagnosed in Scotland in 1979–2003, by thickness, pathological type, and body site at ages under 40, 40–59, and 60 years and over. Melanoma incidence trebled in males from 3.57 to 10.93/105 per year, and increased 2.3-fold in females from 5.60 to 12.96/105 per year. The rate of increase fell in each successive 5-year period. The greatest increase was in males aged 60 years and over at diagnosis. Significant incidence increases were seen in melanomas <1 mm in all three age groups, but those >4 mm only increased significantly at ages 60 years and over. All histological types increased significantly at ages 60 years and over, and in this age group the greatest increase was seen on the head and neck. Five-year disease-free survival improved steadily. Survival figures for 1994–1998 ranged from 93.6% for males and 95.8% for females with tumours <1 mm, to 52.4 and 48.3%, respectively, for those with tumours >4 mm. Over the 25 years, melanoma mortality doubled in males from 1.1 to 2.4/105 per year, but was unchanged in females at 1.5/105 per year. Public education on melanoma is required both for primary prevention and earlier diagnosis, particularly for older males

A comparison of laboratory and in situ methods to determine soil thermal conductivity for energy foundations and other ground heat exchanger applications

Soil thermal conductivity is an important factor in the design of energy foundations and other ground heat exchanger systems. It can be determined by a field thermal response test, which is both costly and time consuming, but tests a large volume of soil. Alternatively, cheaper and quicker laboratory test methods may be applied to smaller soil samples. This paper investigates two different laboratory methods: the steady-state thermal cell and the transient needle probe. U100 soil samples were taken during the site investigation for a small diameter test pile, for which a thermal response test was later conducted. The thermal conductivities of the samples were measured using the two laboratory methods. The results from the thermal cell and needle probe were significantly different, with the thermal cell consistently giving higher values for thermal conductivity. The main difficulty with the thermal cell was determining the rate of heat flow, as the apparatus experiences significant heat losses. The needle probe was found to have fewer significant sources of error, but tests a smaller soil sample than the thermal cell. However, both laboratory methods gave much lower values of thermal conductivity compared to the in situ thermal response test. Possible reasons for these discrepancies are discussed, including sample size, orientation and disturbance

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1∗11:04 and HLA-DPB1∗13:01, and revealed a novel association of HLA-B∗08:01. Stratified analyses showed specific associations of HLA-DQA1∗02:01 with lcSSc, and an exclusive association of HLA-DQA1∗05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1∗08:01 and confirmed the previously reported association of HLA-DRB1∗07:01 with ACA-positive patients, as opposed to the HLA-DPA1∗02:01 and HLA-DQB1∗03:01 alleles associated with ATA presentation. Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression

Effects of PREPARE, a Multi-component, School-Based HIV and Intimate Partner Violence (IPV) Prevention Programme on Adolescent Sexual Risk Behaviour and IPV : Cluster Randomised Controlled Trial

Young South Africans, especially women, are at high risk of HIV. We evaluated the effects of PREPARE, a multi-component, school-based HIV prevention intervention to delay sexual debut, increase condom use and decrease intimate partner violence (IPV) among young adolescents. We conducted a cluster RCT among Grade eights in 42 high schools. The intervention comprised education sessions, a school health service and a school sexual violence prevention programme. Participants completed questionnaires at baseline, 6 and 12 months. Regression was undertaken to provide ORs or coefficients adjusted for clustering. Of 6244 sampled adolescents, 55.3 % participated. At 12 months there were no differences between intervention and control arms in sexual risk behaviours. Participants in the intervention arm were less likely to report IPV victimisation (35.1 vs. 40.9 %; OR 0.77, 95 % CI 0.61-0.99; t(40) = 2.14) suggesting the intervention shaped intimate partnerships into safer ones, potentially lowering the risk for HIV

Differential regulation of neurotrophin expression in human bronchial smooth muscle cells

BACKGROUND: Human bronchial smooth muscle cells (HBSMC) may regulate airway inflammation by secreting cytokines, chemokines and growth factors. The neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been shown to be elevated during airway inflammation and evoke airway hyperresponsiveness. We studied if HBSMC may be a source of NGF, BDNF and NT-3, and if so, how inflammatory cytokines may influence their production. METHODS: Basal and cytokine (IL-1β, IFN-γ, IL-4)-stimulated neurotrophin expression in HBSMC cultured in vitro was quantified. The mRNA expression was quantified by real-time RT-PCR and the protein secretion into the cell culture medium by ELISA. RESULTS: We observed a constitutive NGF, BDNF and NT-3 expression. IL-1β stimulated a transient increase of NGF, while the increase of BDNF had a later onset and was more sustained. COX-inhibitors (indomethacin and NS-398) markedly decreased IL-1β-stimulated secretion of BDNF, but not IL-1β-stimulated NGF secretion. IFN-γ increased NGF expression, down-regulated BDNF expression and synergistically enhanced IL-1β-stimulated NGF expression. In contrast, IL-4 had no effect on basal NGF and BDNF expression, but decreased IL-1β-stimulated NGF expression. NT-3 was not altered by the tested cytokines. CONCLUSION: Taken together, our data indicate that, in addition to the contractile capacity, HBSMC can express NGF, BDNF and NT-3. The expression of these neurotrophins may be differently regulated by inflammatory cytokines, suggesting a dynamic interplay that might have a potential role in airway inflammation

The Drosophila GIPC Homologue Can Modulate Myosin Based Processes and Planar Cell Polarity but Is Not Essential for Development

Epithelia often show, in addition to the ubiquitous apico-basal (A/B) axis, a polarization within the plane of the epithelium, perpendicular to the A/B axis. Such planar cell polarity (PCP) is for example evident in the regular arrangement of the stereocilia in the cochlea of the mammalian inner ear or in (almost) all Drosophila adult external structures. GIPCs (GAIP interacting protein, C terminus) were first identified in mammals and bind to the Gαi GTPase activating protein RGS-GAIP. They have been proposed to act in a G-protein coupled complex controlling vesicular trafficking. Although GIPCs have been found to bind to numerous proteins including Frizzled receptors, which participate in PCP establishment, there is little in vivo evidence for the functional role(s) of GIPCs. We show here that overexpressed Drosophila dGIPC alters PCP generation in the wing. We were however unable to find any binding between dGIPC and the Drosophila receptors Fz1 and Fz2. The effect of overexpressed dGIPC is likely due to an effect on the actin cytoskeleton via myosins, since it is almost entirely suppressed by removing a genomic copy of the Myosin VI/jaguar gene. Surprisingly, although dGIPC can interfere with PCP generation and myosin based processes, the complete loss-of-function of dGIPC gives viable adults with no PCP or other detectable defects arguing for a non-essential role of dGIPC in viability and normal Drosophila development