Deep Learning-Based Data-Point Precise R-Peak Detection in Single-Lead Electrocardiograms.

Low-cost wearables with capability to record electrocardiograms (ECG) are becoming increasingly available. These wearables typically acquire single-lead ECGs that are mainly used for screening of cardiac arrhythmias such as atrial fibrillation. Most arrhythmias are characteruzed by changes in the RR-interval, hence automatic methods to diagnose arrythmia may utilize R-peak detection. Existing R-peak detection methods are fairly accurate but have limited precision. To enable data-point precise detection of R-peaks, we propose a method that uses a fully convolutional dilated neural network. The network is trained and evaluated with manually annotated R-peaks in a heterogeneous set of ECGs that contain a wide range of cardiac rhythms and acquisition noise. 700 randomly chosen ECGs from the PhysioNet/CinC challenge 2017 were used for training (n=500), validation (n=100) and testing (n=100). The network achieves a precision of 0.910, recall of 0.926, and an F1-score of 0.918 on the test set. Our data-point precise R-peak detector may be important step towards fully automatic cardiac arrhythmia detection.Clinical relevance- This method enables data-point precise detection of R-peaks that provides a basis for detection and characterization of arrhythmias.

Preoperative imaging for colorectal liver metastases: a nationwide population-based study.

BACKGROUND: In patients with colorectal liver metastases (CRLM) preoperative imaging may include contrast-enhanced (ce) MRI and [18 F]fluorodeoxyglucose (18 F-FDG) PET-CT. This study assessed trends and variation between hospitals and oncological networks in the use of preoperative imaging in the Netherlands. METHODS: Data for all patients who underwent liver resection for CRLM in the Netherlands between 2014 and 2018 were retrieved from a nationwide auditing database. Multivariable logistic regression analysis was used to assess use of ceMRI, 18 F-FDG PET-CT and combined ceMRI and 18 F-FDG PET-CT, and trends in preoperative imaging and hospital and oncological network variation. RESULTS: A total of 4510 patients were included, of whom 1562 had ceMRI, 872 had 18 F-FDG PET-CT, and 1293 had combined ceMRI and 18 F-FDG PET-CT. Use of ceMRI increased over time (from 9·6 to 26·2 per cent; P < 0·001), use of 18 F-FDG PET-CT decreased (from 28·6 to 6·0 per cent; P < 0·001), and use of both ceMRI and 18 F-FDG PET-CT 16·9 per cent) remained stable. Unadjusted variation in the use of ceMRI, 18 F-FDG PET-CT, and combined ceMRI and 18 F-FDG PET-CT ranged from 5·6 to 100 per cent between hospitals. After case-mix correction, hospital and oncological network variation was found for all imaging modalities. DISCUSSION: Significant variation exists concerning the use of preoperative imaging for CRLM between hospitals and oncological networks in the Netherlands. The use of MRI is increasing, whereas that of 18 F-FDG PET-CT is decreasing.

ANTECEDENTES: En pacientes con metástasis hepáticas colorrectales (colorrectal liver metastases, CRLM), los estudios de imagen preoperatorios pueden incluir resonancia magnética con contraste (ce)MRI y 18 F-FDG-PET-CT. Este estudio evaluó las tendencias y la variación entre los hospitales y las redes oncológicas en el uso de estudios de imagen preoperatorios en los Países Bajos. MÉTODOS: Todos los pacientes que se sometieron a una resección hepática por CRLM en los Países Bajos entre 2014 y 2018 fueron seleccionados a partir de una base de datos a nivel nacional auditada. El análisis de regresión logística multivariable se utilizó para evaluar el uso de ceMRI, de 18 F-FDG-PET-CT y de ceMRI combinado con 18 F-FDG-PET-CT, así como para determinar las tendencias en los estudios de imagen preoperatorios y las variaciones hospitalarias y de la red oncológica. RESULTADOS: En total, se incluyeron 4.510 pacientes, de los cuales 1.562 se sometieron a ceMRI, 872 a 18 F-FDG-PET-CT y 1.293 a ceMRI combinado con 18 F-FDG-PET-CT. El uso de ceMRI aumentó con el tiempo del 9,6% al 26,2% (P < 0,001), el uso de 18 F-FDG-PET-CT disminuyó (25% a 6,0%, P < 0,001) y el uso de ceMRI y 18 F-FDG-PET- CT (17%) se mantuvo estable. La variación no ajustada entre hospitales en el uso de ceMRI, 18 F-FDG-PET-CT y la combinación de ceMRI y 18 F-FDG-PET-CT oscilaba del 5% al 10%. Después de la corrección por case-mix, la variación hospitalaria y de la red oncológica persistía en todas las pruebas de imagen. CONCLUSIÓN: En los Países Bajos existe una variación significativa entre hospitales y redes oncológicas respecto al uso de pruebas de imagen preoperatorias para el CRLM. El uso de MRI está aumentando, mientras que el uso de 18 F-FDG-PET-CT está disminuyendo.

Effects of physical exercise programme on happiness among older people.

ACCESSIBLE SUMMARY: This randomized-controlled trial investigated the effect of physical exercise programme (PEP) on happiness among older adults in Nowshahr, Iran. Results of this study on 120 male and female volunteers showed that an 8-week group physical exercise programme was significantly effective in older adults' happiness. Findings showed that physical exercise programme is so beneficial for increasing older adults' happiness. Physical activity is associated with well-being and happiness. The purpose of this study was to determine the effects of an 8-week long physical exercise programme (PEP) on happiness among older adults in Nowshahr, Iran. This was a randomized control trial study. The participants consisted of a group of 120 male and female volunteers (mean ± SD age: 71 ± 5.86 years) in a convenience sampling among older adults in public parks in Nowshahr, Iran. We randomly allocated them into experimental (n = 60) and control (n = 60) groups. A validated instrument was used to measure well-being and happiness [Oxford Happiness Inventory (OHI)]. Respondents were asked to complete the OHI before and 2 months after implementing PEP. The 8-week PEP was implemented with the intervention group. The statistical analysis of the data was conducted using paired t-test, Fisher's exact test and χ(2). Before the intervention, there was no significant difference in the happiness mean score between the case and control groups; however, after implementing PEP, happiness significantly improved among the experimental group (P = 0.001) and did not improve within the control group (P = 0.79). It can be concluded that PEP had positive effects on happiness among older adults. Planning and implementing of physical activity is so important for older happiness.

Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer.

Our previous study revealed that two splicing factors, polypyrimidine tract-binding protein (PTB) and SRp20, were upregulated in epithelial ovarian cancer (EOC) and knockdown of PTB expression inhibited ovarian tumor cell growth and transformation properties. In this report, we show that knockdown of SRp20 expression in ovarian cancer cells also causes substantial inhibition of tumor cell growth and colony formation in soft agar and the extent of such inhibition appeared to correlate with the extent of suppression of SRp20. Massive knockdown of SRp20 expression triggered remarkable apoptosis in these cells. These results suggest that overexpression of SRp20 is required for ovarian tumor cell growth and survival. Immunohistochemical staining for PTB and SRp20 of two specialized tissue microarrays, one containing benign ovarian tumors, borderline/low malignant potential (LMP) ovarian tumors as well as invasive EOC and the other containing invasive EOC ranging from stage I to stage IV disease, reveals that PTB and SRp20 are both expressed differentially between benign tumors and invasive EOC, and between borderline/LMP tumors and invasive EOC. There were more all-negative or mixed staining cases (at least two evaluable section cores per case) in benign tumors than in invasive EOC, whereas there were more all-positive staining cases in invasive EOC than in the other two disease classifications. Among invasive EOC, the majority of cases were stained all positive for both PTB and SRp20, and there were no significant differences in average staining or frequency of positive cancer cells between any of the tumor stages. Therefore, the expression of PTB and SRp20 is associated with malignancy of ovarian tumors but not with stage of invasive EOC.

Variance components for test-day milk, fat, and protein yield, and somatic cell score for analyzing management information.

Test-day (TD) models are used in most countries to perform national genetic evaluations for dairy cattle. The TD models estimate lactation curves and their changes as well as variation in populations. Although potentially useful, little attention has been given to the application of TD models for management purposes. The potential of the TD model for management use depends on its ability to describe within- or between-herd variation that can be linked to specific management practices. The aim of this study was to estimate variance components for milk yield, milk component yields, and somatic cell score (SCS) of dairy cows in the Ragusa and Vicenza areas of Italy, such that the most relevant sources of variation can be identified for the development of management parameters. The available data set contained 1,080,637 TD records of 42,817 cows in 471 herds. Variance components were estimated with a multilactation, random-regression, TD animal model by using the software adopted by NRS for the Dutch national genetic evaluation. The model comprised 5 fixed effects [region x parity x days in milk (DIM), parity x year of calving x season of calving x DIM, parity x age at calving x year of calving, parity x calving interval x stage of pregnancy, and year of test x calendar week of test] and random herd x test date, regressions for herd lactation curve (HCUR), the animal additive genetic effect, and the permanent environmental effect by using fourth-order Legendre polynomials. The HCUR variances for milk and protein yields were highest around the time of peak yield (DIM 50 to 150), whereas for fat yield the HCUR variance was relatively constant throughout first lactation and decreased following the peak around 40 to 90 DIM for lactations 2 and 3. For SCS, the HCUR variances were relatively small compared with the genetic, permanent environmental, and residual variances. For all the traits except SCS, the variance explained by random herd x test date was much smaller than the HCUR variance, which indicates that the development of management parameters should focus on between-herd parameters during peak lactation for milk and milk components. For SCS, the within-herd variance was greater than the between-herd variance, suggesting that the focus should be on management parameters explaining variances at the cow level. The present study showed clear evidence for the benefits of using a random regression TD model for management decisions.

A pathway analysis tool for analyzing microarray data of species with low physiological information.

Pathway information provides insight into the biological processes underlying microarray data. Pathway information is widely available for humans and laboratory animals in databases through the internet, but less for other species, for example, livestock. Many software packages use species-specific gene IDs that cannot handle genomics data from other species. We developed a species-independent method to search pathways databases to analyse microarray data. Three PERL scripts were developed that use the names of the genes on the microarray. (1) Add synonyms of gene names by searching the Gene Ontology (GO) database. (2) Search the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database for pathway information using this GO-enriched gene list. (3) Combine the pathway data with the microarray data and visualize the results using color codes indicating regulation. To demonstrate the power of the method, we used a previously reported chicken microarray experiment investigating line-specific reactions to Salmonella infection as an example.

Knockdown of polypyrimidine tract-binding protein suppresses ovarian tumor cell growth and invasiveness in vitro.

Polypyrimidine tract-binding protein (PTB) is an RNA-binding protein with multiple functions in the regulation of RNA processing and IRES-mediated translation. We report here overexpression of PTB in a majority of epithelial ovarian tumors revealed by immunoblotting and tissue microarray (TMA) staining. By western blotting, we found that PTB was overexpressed in 17 out of 19 ovarian tumor specimens compared to their matched-normal tissues. By TMA staining, we found PTB expression in 38 out of 44 ovarian cancer cases but only in two out of nine normal adjacent tissues. PTB is also overexpressed in SV40 large T-antigen immortalized ovarian epithelial cells compared to normal human ovarian epithelial cells. Using doxycycline-inducible small interfering RNA technology, we found that knockdown of PTB expression in the ovarian tumor cell line A2780 substantially impaired tumor cell proliferation, anchorage-independent growth and in vitro invasiveness. These results suggest that overexpression of PTB is an important component of the multistep process of tumorigenesis, and might be required for the development and maintenance of epithelial ovarian tumors. Moreover, because of its novel role in tumor cell growth and invasiveness, shown here for the first time, PTB may be a novel therapeutic target in the treatment of ovarian cancer.

Review article: Gastro-oesophageal reflux disease--application of the concept of complete remission.

BACKGROUND: Therapeutic success in the treatment of gastro-oesophageal reflux disease cannot be measured by endoscopic healing or symptomatic relief alone. Assessment of treatment efficacy should be based on symptomatic relief and endoscopic healing. As most questionnaires focus on heartburn, it is important to stress that there is more to gastro-oesophageal reflux disease than just heartburn. The 'complete remission' concept was recently introduced; an approach in which endoscopic appearances and symptomatic relief are integrated, thus allowing the full gastro-oesophageal reflux disease picture and its changes over time to be described in a simple and accurate manner. Complete remission is defined as the absence of both oesophagitis and symptoms. ReQuest, a relatively new questionnaire acceptable as a clinical endpoint in trials, seems to be of use in daily practice. AIM: To review the utility of the ReQuest questionnaire. RESULTS: This questionnaire assesses the gastro-oesophageal reflux disease symptom profile using 67 symptom descriptions adapted from patients' view, doctors' view, clinical trials and from the literature. Individual symptoms are reduced to seven dimensions by factor analysis and expert consensus. This gives insight into multiple symptoms over time as well as individual patient profiles. ReQuest determines symptom relief using a gastro-oesophageal reflux disease symptom threshold. This unique concept allows the doctor to measure the time to first symptom relief and also to sustained symptom relief. CONCLUSIONS: ReQuest makes it possible to evaluate the complete symptom spectrum in patients with non-erosive oesophageal reflux disease and gastro-oesophageal reflux disease. ReQuest is available for daily practice to use for comparability with regard to treatment efficacy.

Comparison of prenatal muscle tissue expression profiles of two pig breeds differing in muscle characteristics.

The objective of this study was to compare purebred Duroc and Pietrain prenatal muscle tissue transcriptome expression levels at different stages of prenatal development to gain insight into the differences in muscle tissue development in these pig breeds. Commercial western pig breeds have been selected for muscle growth for the past 2 decades. Pig breeds differ for their muscle phenotypes (i.e., myofiber numbers and myofiber types). Duroc and Pietrain pig breeds are extremes; Duroc pigs have redder muscle fiber types with more intramuscular fat, and Pietrain pigs have faster-growing and whiter muscle fiber types. Pietrain pigs are more muscular than Duroc pigs, whereas Duroc pigs are fatter than Pietrain pigs. The genomic background underlying these breed-specific differences is poorly known. Myogenesis is a complex exclusive prenatal process involving proliferation and differentiation (i.e., fusion) of precursor cells called myoblasts. We investigated the difference in the prenatal muscle-specific transcriptome profiles of Duroc and Pietrain pigs using microarray technology. The microarray contained more than 500 genes affecting myogenesis, energy metabolism, muscle structural genes, and other genes from a porcine muscle cDNA library. The results indicated that the expression of the myogenesis-related genes was greater in early Duroc embryos than in early Pietrain embryos (14 to 49 d of gestation), whereas the opposite was found in late embryos (63 to 91 d of gestation). These findings suggest that the myogenesis process is more intense in early Duroc embryos than in Pietrain embryos but that myogenesis is more intense in late Pietrain fetuses than in Duroc fetuses. Transcriptomes of muscle structural genes followed that pattern. The energy metabolism genes were expressed at a higher level in prenatal Pietrain pigs than in prenatal Duroc pigs, except for d 35, when the opposite situation was found. Fatty acid metabolism genes were expressed at a higher level in early (14 to 49 d of gestation) Duroc embryos than in Pietrain embryos. Better understanding of the genomic regulation of tissue formation leads to improved knowledge of the genome under selection and may lead to directed breed-specific changes in the future.

The dragged-fovea diplopia syndrome: clinical characteristics, diagnosis, and treatment.

PURPOSE: To identify the clinical characteristics of the dragged-fovea diplopia syndrome, to introduce a simple diagnostic test that aids in the evaluation of such patients, and to provide a simple treatment option to improve the diplopia in some of these patients. DESIGN: Retrospective, observational case series. PARTICIPANTS: Ninety-five affected eyes in 83 consecutive patients seen between January 1, 1993, and August 9, 2004, who were diagnosed with the dragged-fovea diplopia syndrome at one institution. METHODS: We reviewed the records of 222 patients who have been seen in the Krieger Children's Eye Center at The Wilmer Institute since 1993 with a diagnosis of maculopathy, internal limiting membrane, or dragged fovea. We collected ocular findings and history for those patients who reported binocular diplopia that was not amenable to prism therapy and not secondary to acquired strabismus. MAIN OUTCOME MEASURES: We recorded the presence of metamorphopsia on Amsler grid testing or other clinical evidence of macular wrinkling, response to prism trial, response to the small-field central fusion test (lights on-off test), and response to partial occlusion with Scotch Satin tape (3M Co., St. Paul, MN). RESULTS: Ninety-five affected eyes in 83 patients met the criteria for inclusion in the study. All patients who were tested with the lights on-off test (n = 69) responded positively, demonstrating rapid central fusion with room lights off, and recurrence of central diplopia with peripheral fusion with room lights on. Forty-six patients (of 64 tested) were receptive to monocular occlusion with Scotch Satin tape. CONCLUSIONS: The dragged-fovea diplopia syndrome consists of central diplopia in the presence of peripheral fusion, secondary to dragging of the fovea in one or both eyes by retinal disease. The central diplopia cannot be eliminated by prism therapy or eye muscle surgery. The lights on-off test has proved pathognomonic for this syndrome, and many patients have benefited from partial monocular occlusion with Scotch Satin tape.

Getting to the membrane: how is co-translational protein targeting to the endoplasmic reticulum regulated?

Co-translational protein targeting to the endoplasmic reticulum requires the signal-recognition particle, its cognate receptor and the translocation channel. Co-ordination of the targeting process necessitates the interaction of these components with each other and with the ribosome. These interactions are regulated by three GTPases, which act in concert, ensuring the fidelity of the targeting process.

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a.

Here, we describe a novel spontaneous autosomal recessive mutation in the mouse that is characterized by skeletal and cardiac muscle degeneration. We have named this mutant degenerating muscle (dmu). At birth, mutant mice are indistinguishable from their normal littermates. Thereafter, the disease progresses rapidly and a phenotype is first observed at approximately 11 days after birth; the dmu mice are weak and have great difficulty in moving. The principal cause of the lack of mobility is muscle atrophy and wasting in the hindquarters. Affected mice die at or around the time of weaning of unknown causes. Histopathological observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. Using linkage analysis, we have mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Interestingly, scapuloperoneal muscular dystrophy (SPMD) in humans has been linked to this region. SPMD patients with associated cardiomyopathy have also been described in the past. Initial analysis of candidate genes on mouse chromosome 15 reveal that although intact transcripts for Scn8a, the gene encoding the sodium channel 8a subunit, are present in dmu mice, their levels are dramatically reduced. Furthermore, genetic complementation crosses between dmu and med (mutation in Scn8a) mice revealed that they are allelic. Our results suggest that at least a portion of the dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new allele of Scn8a.

Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein.

The microtubule-associated tau proteins represent a family of closely related phosphoproteins that become enriched in the axons during brain development. In Alzheimer's disease (AD), tau aggregates somatodendritically in paired helical filaments in a hyperphosphorylated form. Most of the sites that are phosphorylated to a high extent in paired helical filament tau are clustered in the proline-rich region (P-region; residues 172--251) and the C-terminal tail region (C-region; residues 368--441) that flank tau's microtubule-binding repeats. This might point to a role of a region-specific phosphorylation cluster for the pathogenesis of AD. To determine the functional consequences of such modifications, mutated tau proteins were produced in which a P- or C-region-specific phosphorylation cluster was simulated by replacement of serine/threonine residues with glutamate. We show that a phosphorylation-mimicking glutamate cluster in the P-region is sufficient to block microtubule assembly and to inhibit tau's interaction with the dominant brain phosphatase protein phosphatase 2A isoform AB alpha C. P-region-specific mutations also decrease tau aggregation into filaments and decrease tau's process-inducing activity in a cellular transfection model. In contrast, a phosphorylation-mimicking glutamate cluster in the C-region is neutral with regard to these activities. A glutamate cluster in both the P- and C-regions induces the formation of SDS-resistant conformational domains in tau and suppresses tau's interaction with the neural membrane cortex. The results indicate that modifications in the proline-rich region are sufficient to induce the functional deficiencies of tau that have been observed in AD. They suggest that phosphorylation of the proline-rich region has a crucial role in mediating tau-related changes during disease.

The accuracy of the Helicobacter pylori stool antigen test in diagnosing H. pylori in treated and untreated patients.

OBJECTIVE AND DESIGN: To evaluate the performance of the Helicobacter pylori stool antigen test (HpSA test) in detecting H. pylori infection and monitoring the effect of treatment. This was done in two separate studies using either a biopsy or the 13C-urea breath test based 'gold standard' (in untreated and treated patients, respectively). SETTING: Endoscopy units of two general hospitals. PATIENTS: One hundred and twenty-eight dyspeptic patients undergoing endoscopy in the first study. Sixty-five patients receiving anti-H. pylori treatment in the second study. RESULTS: Sensitivity and specificity in untreated patients were 96.3% and 81.8%, respectively. Seven days after treatment, these figures were 20% and 95%, and 4 weeks after treatment they were 40% and 95%. CONCLUSION: The HpSA test is accurate in untreated patients but fails in monitoring treatment success.

Pharmacotherapeutic options in inflammatory bowel disease: an update.

Chronic inflammatory bowel disease (IBD) refers to two diseases: Crohn's disease (CD) and ulcerative colitis (UC). The etiology of IBD remains unknown. The understanding of the pathogenesis has expanded greatly over the last decade. The combination of genetic risk factors, abnormalities in the immune system, vascular and neural factors, and random environmental factors may all play an important role. Most treatments currently in use have multiple action. The choice of appropriate medical treatment is determined by the status (inductive or maintenance therapy) and severity of the disease and the potential for toxicity. Despite the variety of medical therapies available for the treatment of IBD, none is ideal. Ongoing research into the well-established drugs, as well as novel agents with more precise targets, may contribute to an optimal therapy of IBD in the near future. In this paper the current (5-aminosalicylates, glucocorticosteroids, thioguanine derivatives, methotrexate, cyclosporin and infliximab) as well as some of the new (mycophenolate mofetil and thalidomide) therapeutic options are reviewed.

SRbeta coordinates signal sequence release from SRP with ribosome binding to the translocon.

Protein targeting to the endoplasmic reticulum (ER) membrane is regulated by three GTPases, the 54 kDa subunit of the signal recognition particle (SRP) and the alpha- and beta-subunits of the SRP receptor (SR). Using a soluble form of SR and an XTP-binding mutant of SRbeta, we show that SRbeta is essential for protein translocation across the ER membrane. SRbeta can be cross-linked to a 21 kDa ribosomal protein in its empty and GDP-bound state, but not when GTP is bound. GTP binding to SRbeta is required to induce signal sequence release from SRP. This is achieved by the presence of the translocon, which changes the interaction between the 21 kDa ribosomal protein and SRbeta and thereby allows SRbeta to bind GTP. We conclude that SRbeta coordinates the release of the signal sequence from SRP with the presence of the translocon.

Scp160p, an RNA-binding, polysome-associated protein, localizes to the endoplasmic reticulum of Saccharomyces cerevisiae in a microtubule-dependent manner.

Scp160p is an RNA-binding protein containing 14 tandemly repeated heterogenous nuclear ribonucleoprotein K-homology domains, which are implicated in RNA binding. Scp160p interacts with free and membrane-bound polysomes that are dependent upon the presence of mRNA. Despite its presence on cytosolic polysomes, Scp160p is predominantly localized to the endoplasmic reticulum (ER). Accumulation of Scp160p-ribosome complexes at the ER requires the function of microtubules but is independent of the actin cytoskeleton. We propose that the multi-K-homology-domain protein Scp160p functions as an RNA binding platform, interacting with polysomes that are transported to the ER.

The ateliotic macula: a newly recognized developmental anomaly.

PURPOSE: We present a macular phenotype resulting from 1 or more abnormalities in the developmental pathway of the central retina. METHODS: We describe the clinical and genetic characteristics of 7 patients observed since shortly after birth with regard to visual acuity, refractive error, anterior segment status, retinal findings including foveal structure, and natural history. RESULTS: The patients varied in age from 18 months to 18 years. All patients were examined for the first time during their first year of life and by us at the age of 5 years or younger. The longest follow-up period was 16 years. The abnormal appearance of the macula consisted of thinning of the retina, rarefication of the pigment epithelium with excess visibility of the large choroidal vessels, and absence of the foveal reflex. The visual acuities varied from 20/20 in the better eye to light perception. A retinal detachment was noted in 1 patient at age 2 1/2 years. The refractive errors varied from -2.50 to -16.50 diopters of spherical equivalent. The disease was limited to the retina in 4 patients. In 2 patients, however, developmental abnormalities of the anterior segment were also present; they consisted of malformation of the iris in 1 patient and Peters' anomaly in the other. The electroretinogram (ERG) showed reduced but not absent photopic responses and some reduction in scotopic responses. CONCLUSION: The phenotype of ateliotic macula is being defined as characterized by an unfinished or primordial appearance. In the 7 patients studied, visual loss was noted shortly after birth. The visual outcome was variable with regard to visual acuity, but many patients showed improvement. There was no evidence of significant worsening of the disease with age except in 1 patient who had a retinal detachment. The ERG responses showed primarily photopic but also scotopic changes. The better-preserved ERG differentiates this disorder from Leber's congenital amaurosis.

Genetic parameters of legendre polynomials for first parity lactation curves.

Variance components of the covariance function coefficients in a random regression test-day model were estimated by Legendre polynomials up to a fifth order for first-parity records of Dutch dairy cows using Gibbs sampling. Two Legendre polynomials of equal order were used to model the random part of the lactation curve, one for the genetic component and one for permanent environment. Test-day records from cows registered between 1990 to 1996 and collected by regular milk recording were available. For the data set, 23,700 complete lactations were selected from 475 herds sired by 262 sires. Because the application of a random regression model is limited by computing capacity, we investigated the minimum order needed to fit the variance structure in the data sufficiently. Predictions of genetic and permanent environmental variance structures were compared with bivariate estimates on 30-d intervals. A third-order or higher polynomial modeled the shape of variance curves over DIM with sufficient accuracy for the genetic and permanent environment part. Also, the genetic correlation structure was fitted with sufficient accuracy by a third-order polynomial, but, for the permanent environmental component, a fourth order was needed. Because equal orders are suggested in the literature, a fourth-order Legendre polynomial is recommended in this study. However, a rank of three for the genetic covariance matrix and of four for permanent environment allows a simpler covariance function with a reduced number of parameters based on the eigenvalues and eigenvectors.