Bio-knowledge-based filters improve residue-residue contact prediction accuracy.

Motivation: Residue-residue contact prediction through direct coupling analysis has reached impressive accuracy, but yet higher accuracy will be needed to allow for routine modelling of protein structures. One way to improve the prediction accuracy is to filter predicted contacts using knowledge about the particular protein of interest or knowledge about protein structures in general. Results: We focus on the latter and discuss a set of filters that can be used to remove false positive contact predictions. Each filter depends on one or a few cut-off parameters for which the filter performance was investigated. Combining all filters while using default parameters resulted for a test set of 851 protein domains in the removal of 29% of the predictions of which 92% were indeed false positives. Availability and implementation: All data and scripts are available at http://comprec-lin.iiar.pwr.edu.pl/FPfilter/. Supplementary information: Supplementary data are available at Bioinformatics online.

Impact of a neuro-intensive care service for newborns.

BACKGROUND: Advances in treating the injured neonatal brain have given rise to neuro-intensive care services for newborns. This study assessed the impact of one such service in a cohort of newborns treated with therapeutic hypothermia. METHODS: Our newborn neuro-intensive care service was started in November 2012. From January 2008 to October 2016, a cohort of 158 newborns was treated with therapeutic hypothermia, 29 before and 129 after the inception of the service. This study compared the outcomes of newborns treated by the service with those of newborns treated before. Multivariate regression analysis associating length-of-stay and treatment pre- or post-service was adjusted for five-minute Apgar score, time-to-target temperature, seizures, and mortality. RESULTS: The neuro-intensive care service was also associated with a decrease in mortality (17% before service to 5.4% with the service, p = 0.03), though this association is likely multifactorial and reflects the application of therapeutic hypothermia to a wider variety of patients. However, the service was independently associated with decreased length-of-stay (mean 22 pre-service to 13 days with the service, p < 0.0005.)CONCLUSIONS:The service educated referring hospitals in recognizing therapeutic hypothermia candidates, which increased the number of treated newborns, and created a number of procedures to streamline the delivery of treatment. While the increasing number and variety of patients treated could spuriously reduce length-of-stay, length-of-stay was still significantly reduced after adjustment, providing evidence that neuro-intensive care services for newborns can improve hospital outcomes.

Forecasting residue-residue contact prediction accuracy.

MOTIVATION: Apart from meta-predictors, most of today's methods for residue-residue contact prediction are based entirely on Direct Coupling Analysis (DCA) of correlated mutations in multiple sequence alignments (MSAs). These methods are on average ∼40% correct for the 100 strongest predicted contacts in each protein. The end-user who works on a single protein of interest will not know if predictions are either much more or much less correct than 40%, which is especially a problem if contacts are predicted to steer experimental research on that protein. RESULTS: We designed a regression model that forecasts the accuracy of residue-residue contact prediction for individual proteins with an average error of 7 percentage points. Contacts were predicted with two DCA methods (gplmDCA and PSICOV). The models were built on parameters that describe the MSA, the predicted secondary structure, the predicted solvent accessibility and the contact prediction scores for the target protein. Results show that our models can be also applied to the meta-methods, which was tested on RaptorX. AVAILABILITY AND IMPLEMENTATION: All data and scripts are available from http://comprec-lin.iiar.pwr.edu.pl/dcaQ/. CONTACT: malgorzata.kotulska@pwr.edu.pl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Congenital syphilis in neonates with nonreactive nontreponemal test results.

OBJECTIVE: Infants whose mothers had syphilis during pregnancy were studied to determine how often exposed newborns with normal physical examinations and nonreactive nontreponemal serologic tests had abnormal laboratory or radiographic studies. STUDY DESIGN: Retrospective analysis of prospectively collected data from infants born to mothers with syphilis and had a normal examination and a nonreactive nontreponemal test. Some infants had IgM immunoblotting, PCR testing or rabbit infectivity testing (RIT) performed. RESULTS: From 1984 to 2002, 115 infants had a nonreactive serum Venereal Disease Research Laboratory (VDRL)/rapid plasma reagin (RPR) test and a normal physical examination at birth. Among 87 infants born to mothers who had untreated syphilis, 4 had a positive serum IgM immunoblot or PCR test, but none had spirochetes recovered by RIT. Two infants had anemia, one had an elevated serum alanine aminotransferase concentration and one with Down's syndrome had direct hyperbilirubinemia. Among 14 infants born to mothers treated <4 weeks before delivery, none had abnormal laboratory or radiographic tests, although 1 of 11 had a reactive serum IgM immunoblot. Among 14 infants born to mothers treated ⩾4 weeks before delivery, none had abnormal laboratory or radiographic tests. CONCLUSION: Newborns with normal physical examination and nonreactive nontreponemal test results are unlikely to have abnormalities detected on conventional laboratory and radiographic testing.

Correlated mutations select misfolded from properly folded proteins.

MOTIVATION: The recently developed direct coupling analysis (DCA) method has greatly improved the accuracy with which residue-residue contacts can be predicted from multiple sequence alignments. Contact prediction accuracy, though, is still often not sufficient for complete ab initio protein structure prediction. DCA can, however, support protein structure studies in several ways. RESULTS: We show that DCA can select the better structure from among properly folded and misfolded variants. This idea was tested by comparing obsolete PDB files with their more correctly folded successors and by the comparison of structures with deliberately misfolded decoy models from the Decoys 'R' Us database. The DCA method systematically predicts more contacts for properly folded structures than for misfolded ones. The method works much better for X-ray structures than for NMR structures. AVAILABILITY AND IMPLEMENTATION: All data are available from http://comprec-lin.iiar.pwr.edu.pl/dcaVSmisfolds/ and http://swift.cmbi.ru.nl/dcaVSmisfolds/ . CONTACT: malgorzata.kotulska@pwr.edu.pl . SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Astronomy. ASASSN-15lh: A highly super-luminous supernova.

We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± 0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.

Unveiling the optical properties of a metamaterial synthesized by electron-beam-induced deposition.

Direct writing using a focused electron beam allows for fabricating truly three-dimensional structures of sub-wavelength dimensions in the visible spectral regime. The resulting sophisticated geometries are perfectly suited for studying light-matter interaction at the nanoscale. Their overall optical response will strongly depend not only on geometry but also on the optical properties of the deposited material. In the case of the typically used metal-organic precursors, the deposits show a substructure of metallic nanocrystals embedded in a carbonaceous matrix. Since gold-containing precursor media are especially interesting for optical applications, we experimentally determine the effective permittivity of such an effective material. Our experiment is based on spectroscopic measurements of planar deposits. The retrieved permittivity shows a systematic dependence on the gold particle density and cannot be sufficiently described using the common Maxwell-Garnett approach for effective medium.

A strong ultraviolet pulse from a newborn type Ia supernova.

Type Ia supernovae are destructive explosions of carbon-oxygen white dwarfs. Although they are used empirically to measure cosmological distances, the nature of their progenitors remains mysterious. One of the leading progenitor models, called the single degenerate channel, hypothesizes that a white dwarf accretes matter from a companion star and the resulting increase in its central pressure and temperature ignites thermonuclear explosion. Here we report observations with the Swift Space Telescope of strong but declining ultraviolet emission from a type Ia supernova within four days of its explosion. This emission is consistent with theoretical expectations of collision between material ejected by the supernova and a companion star, and therefore provides evidence that some type Ia supernovae arise from the single degenerate channel.

The bright optical flash and afterglow from the gamma-ray burst GRB 130427A.

The optical light generated simultaneously with x-rays and gamma rays during a gamma-ray burst (GRB) provides clues about the nature of the explosions that occur as massive stars collapse. We report on the bright optical flash and fading afterglow from powerful burst GRB 130427A. The optical and >100-megaelectron volt (MeV) gamma-ray flux show a close correlation during the first 7000 seconds, which is best explained by reverse shock emission cogenerated in the relativistic burst ejecta as it collides with surrounding material. At later times, optical observations show the emergence of emission generated by a forward shock traversing the circumburst environment. The link between optical afterglow and >100-MeV emission suggests that nearby early peaked afterglows will be the best candidates for studying gamma-ray emission at energies ranging from gigaelectron volts to teraelectron volts.

A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer.

BACKGROUND: Pomegranate juice has been associated with PSA doubling time (PSADT) elongation in a single-arm phase II trial. This study assesses biological activity of two doses of pomegranate extract (POMx) in men with recurrent prostate cancer, using changes in PSADT as the primary outcome. METHODS: This randomized, multi-center, double-blind phase II, dose-exploring trial randomized men with a rising PSA and without metastases to receive 1 or 3 g of POMx, stratified by baseline PSADT and Gleason score. Patients (104) were enrolled and treated for up to 18 months. The intent-to-treat (ITT) population was 96% white, with median age 74.5 years and median Gleason score 7. This study was designed to detect a 6-month on-study increase in PSADT from baseline in each arm. RESULTS: Overall, median PSADT in the ITT population lengthened from 11.9 months at baseline to 18.5 months after treatment (P < 0.001). PSADT lengthened in the low-dose group from 11.9 to 18.8 months and 12.2 to 17.5 months in the high-dose group, with no significant difference between dose groups (P = 0.554). PSADT increases >100% of baseline were observed in 43% of patients. Declining PSA levels were observed in 13 patients (13%). In all, 42% of patients discontinued treatment before meeting the protocol-definition of PSA progression, or 18 months, primarily due to a rising PSA. No significant changes occurred in testosterone. Although no clinically significant toxicities were seen, diarrhea was seen in 1.9% and 13.5% of patients in the 1- and 3-g dose groups, respectively. CONCLUSIONS: POMx treatment was associated with ≥ 6 month increases in PSADT in both treatment arms without adverse effects. The significance of this on-study slowing of PSADT remains unclear, reinforcing the need for placebo-controlled studies in this patient population.

The initial zones of the atrioventricular node: really neglected anatomical features of potential clinical significance?

The constant evolution of medical knowledge and accompanying development of diagnostic and treatment possibilities for arrhythmias and conduction disturbances has reawakened interest in the structure and function of the conduction system of the human heart, especially in the region of the atrioventricular (AV) junction and within the junction itself. Of the large number of studies dealing with the AV junction few focus on the initial zones of the AV node. These were described for the first time by Tawara in 1906. Similarly, Anderson et al. distinguished two origins of the AV node, the left one running towards the basis of the mitral valve and the right one leading towards the tricuspid valve. The differences in length and scale could be the result of the adoption of different reference points. The study was carried out on the material of 50 human hearts, of both sexes and ranging in age from 22 to 93, which were fixed in 10% formalin and 98% ethanol solution. The tissue obtained was fixed in the 10% formalin solution and, after being sunk in the paraffin, was cut into layers of about 10 mum thick. According to the age of the hearts, every 10(th) or 6(th) section was stained by the Masson-Goldner method. The preparations were examined under a LEICA 2000 and BIOLAR 2 microscope at magnifications of 2x to 400x. Each of the 50 examined hearts contained the atrioventricular node and its initial parts. We observed that the initial zone of the AV node is created by an assembly of cells typical for a conduction system that can create three groups that are initially independent of each other and are always arranged around the AV nodal artery. In all the hearts examined we found at least two initial parts of the node: the superior and inferior. These two groups were present in 45 hearts (90%). In the last 5 cases (10%) there was also a middle group. No cases were found either with a single initial group or without any initial groups. In the sections examined the superior group appeared to be first in 27 hearts (54%), while in 23 cases (46%) the inferior group was first. The length of each group was measured from its first appearance to its first direct contact with the second part. The length of the superior part varied from 0.15 to 2.91 mm (mean 0.90 +/- 0.6 mm), the inferior from 0.11 to 2.41 mm (mean 0.88 +/- 0.6 mm) and the middle from 0.67 to 2.21 mm (mean 1.04 +/- 0.7 mm). As mentioned above, in all 50 hearts there was a direct connection between the atrial muscle and the upper origin of AV node. Furthermore, in all sections (100%) the same part of the interatrial septal muscle was connected to the compact part of the node. Additionally, in 3 cases (6%) we were able to observe direct connections between the muscle fibres running from the fasciculus limbicus inferior to the initial zone of the AV node: in 2 cases (4%) with the superior group and in 1 case (2%) with the inferior group. In 8% of the material the atrial muscle of the supra-orificial zone made direct contact with the superior initial group and the compact zone of the node and in 10% there was contact between the suborificial muscle and the inferior group and the compact part of the node. This configuration was not observed in relation to the middle and inferior groups.

Energy input and response from prompt and early optical afterglow emission in gamma-ray bursts.

The taxonomy of optical emission detected during the critical first few minutes after the onset of a gamma-ray burst (GRB) defines two broad classes: prompt optical emission correlated with prompt gamma-ray emission, and early optical afterglow emission uncorrelated with the gamma-ray emission. The standard theoretical interpretation attributes prompt emission to internal shocks in the ultra-relativistic outflow generated by the internal engine; early afterglow emission is attributed to shocks generated by interaction with the surrounding medium. Here we report on observations of a bright GRB that, for the first time, clearly show the temporal relationship and relative strength of the two optical components. The observations indicate that early afterglow emission can be understood as reverberation of the energy input measured by prompt emission. Measurements of the early afterglow reverberations therefore probe the structure of the environment around the burst, whereas the subsequent response to late-time impulsive energy releases reveals how earlier flaring episodes have altered the jet and environment parameters. Many GRBs are generated by the death of massive stars that were born and died before the Universe was ten per cent of its current age, so GRB afterglow reverberations provide clues about the environments around some of the first stars.

A link between prompt optical and prompt gamma-ray emission in gamma-ray bursts.

The prompt optical emission that arrives with the gamma-rays from a cosmic gamma-ray burst (GRB) is a signature of the engine powering the burst, the properties of the ultra-relativistic ejecta of the explosion, and the ejecta's interactions with the surroundings. Until now, only GRB 990123 had been detected at optical wavelengths during the burst phase. Its prompt optical emission was variable and uncorrelated with the prompt gamma-ray emission, suggesting that the optical emission was generated by a reverse shock arising from the ejecta's collision with surrounding material. Here we report prompt optical emission from GRB 041219a. It is variable and correlated with the prompt gamma-rays, indicating a common origin for the optical light and the gamma-rays. Within the context of the standard fireball model of GRBs, we attribute this new optical component to internal shocks driven into the burst ejecta by variations of the inner engine. The correlated optical emission is a direct probe of the jet isolated from the medium. The timing of the uncorrelated optical emission is strongly dependent on the nature of the medium.

An association between the matrix metalloproteinase 1 promoter gene polymorphism and lymphnode metastasis in breast cancer.

A single guanine insertion (1G/2G polymorphism) in the promoter of the matrix metalloproteinase (MMP-1) gene creates a binding site for the transcription factor and may affect the level of transcription of MMP-1. An elevated level of MMP-1 in cancer cells may facilitate their invasion and contribute to metastasis. To evaluate the contribution of 1G/2G polymorphism in the development and/or progression of breast cancer we genotyped 135 subjects with breast cancer. The 1G/2G polymorphism was determined by the method based on restriction endonuclease digestion. We found that the frequency of the 2G allele was higher in lymphnode-metastasis patients than in the group without metastasis (p < 0.001). We did not find differences between distribution of the genotypes and frequencies of alleles in cancer patients and in healthy subjects served as control. Our results suggest that allele 2G may be associated with lymphnode metastasis in patients with breast cancer and therefore it can be considered as a prognostic marker in this disease.

Treatment of high-risk superficial bladder cancer with maintenance bacille Calmette-Guérin therapy: preliminary results.

OBJECTIVE: To evaluate, in a prospective study, the effects and results of maintenance therapy with bacille Calmette-Guérin (BCG) in treating patients with high-risk superficial bladder cancer. PATIENTS AND METHODS: In all, 155 patients were enrolled in a randomized study of transurethral resection alone (53) or combined with intravesical BCG (102) as a treatment for superficial bladder cancer. BCG was administered for six consecutive weeks followed by three weekly instillations in months 3, 6, 12, 18, 24, 30 and 36 after resection. Recurrence, progression, prognostic factors and side-effects were assessed and analysed. RESULTS: After a median (range) follow-up of 23 (6-42) months, 83 of the 102 patients treated with BCG (81%) were disease-free, compared with 24 of the 53 treated with resection alone (45%). There was also a significant difference in tumour progression and time to progression between the trial arms. The disease progressed in eight patients (8%) treated with BCG and in 12 (23%) of those treated by resection alone. Independent risk factors for progression were DNA ploidy status and stage. Only the completion of treatment was predictive of outcome (risk of recurrence) for patients treated with BCG. CONCLUSION: Maintenance BCG therapy was better than resection alone in reducing the incidence of recurrence and progression in patients with high-risk superficial bladder cancer.

The activity of beta-hexosaminidase (uHex) and gamma-glutamyl-transferase (uGGT) in urine as non-invasive markers of chronic alcohol abuse: I. Alcohol-dependent subjects.

It has been demonstrated that in alcohol-dependent men the uHex test is one of the most powerful discriminating tools, while uGGT has a discriminating power similar to that of sHex but worse than that of uHex, sGGT and s%CDT. Receiver Operating Characteristic (ROC) areas under the curves (AUC) for uHex, uGGT, s%CDT, sHex and sGGT were 0.92, 0.79, 0.88, 0.79 and 0.92, respectively. Due to their good parameters, low cost, ease of use and non-invasive character the uHex and uGGT tests are useful tools for the detection of chronic alcohol abuse.

Anterior region of the atrioventricular perinodal area in relation to radiofrequency ablation procedures.

Atrioventricular nodal reentry tachycardia base on reentry circulation in nodal-perinodal area. The radical treatment of choice is radiofrequency ablation. Procedure approached from the anterior-superior (fast) region sufficient a few seconds of energy delivery for success, however this can result in A-V block. The possibility that arrhythmias substrate may lie very superficially (success of ablation) and damage the normal structures (complication) in the perinodal region must be considered. In order to confirm this hypothesis we examined the autopsy material of 100 normal hearts, both sexes from 18 to 105 years of age (control) and 50 hearts with A-V total block 45-95 years of age (block). We paid attention to the morphology of the nodal artery (NA), atrial inputs (AI) and transitional inputs (TI). It was observed that NA at the level of the central fibrous body was positioned in 94% in the central and in 6% in the inferior part of Koch's triangle. It was removed from the endocardium 3-6 mm in control and 2-5 mm in block group respectively (NS). In the perinodal area we distinguished AI that directly joined the A-V compact node: superficial (right part of the interatrial septum) or deep (left part). The former occurred in 100% of controls and in 80% of block groups (NS), and the latter in 80% of control group and in 34% in block respectively (p < 0.05). The real substrate of arrhythmia in anterior-superior region lies very superficially and far from the conduction tissue; NA in examined hearts was lying deep beneath the endocardium; ablation close to the node could result in A-V block.

[Evaluation of coagulation and fibrinolysis systems in women at peri- and postmenopausal age qualified for hormone replacement therapy]. / Ocena ukladu krzepniecia i fibrynolizy u kobiet w okresie okolo- i pomenopauzalnym kwalifikowanych do hormonoterapii zastepczej.

OBJECTIVE: The aim of the study was to evaluate coagulation and fibrinolysis systems in peri- and postmenopausal women who were qualified for hormone replacement therapy. MATERIALS AND METHODS: In sixty eight peri- and postmenopausal women qualified for hormone replacement therapy under study some coagulation and fibrinolysis parameters were measured in serum--platelet count, prothrombin time, prothrombin ratio, INR, APTT, thrombin time (TT), fibrinogen, D-dimers, TAT, factor VII, activity of antithrombin III, activity of protein C and protein S, PAI-1 and t-PA concentration. Controls were 26 healthy, reproductive women. RESULTS: Out of fifteen examined coagulation and fibrinolysis parameters in six cases there were statistically significant differences between menopausal women and controls:--APTT and TT were shortened (but within normal range) in menopausal group than in controls;--concentration of fibrinogen in menopausal group (also within normal range) was higher than in controls;--activity of factor VII was risen (and outside normal range) in the examined group in comparison to the controls;--activity of protein S was lower in menopausal than in reproductive women;--also concentration of t-PA was lower in the examined group. CONCLUSIONS: 1. Differences in the values of coagulation and fibrinolytic parameters between the menopausal and reproductive groups of women may testify to the increased risk of thrombus formation in women at peri- and postmenopausal age. 2. Impaired fibrinolysis (low t-PA, high PAI-1) together with the rise in activity of factor VII can contribute to the development of ischaemic heart disease in menopausal women.

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.

BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.