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Flaring episodes in blazars represent one of the most violent processes observed in extra-galactic objects. Studies of such events shed light on the energetics of the physical processes occurring in the innermost regions of blazars, which cannot otherwise be resolved by any current instruments. In this work, we present some of the largest and most rapid flares captured in the optical band in the blazars 3C 279, OJ 49, S4 0954+658, TXS 1156+295 and PG 1553+113. The source flux was observed to increase by nearly ten times within a timescale of a few weeks. We applied several methods of time series analysis and symmetry analysis. Moreover, we also performed searches for periodicity in the light curves of 3C 279, OJ 49 and PG 1553+113 using the Lomb-Scargle method and found plausible indications of quasi-periodic oscillations (QPOs). In particular, the 33- and 22-day periods found in 3C 279, i.e. a 3:2 ratio, are intriguing. These violent events might originate from magnetohydrodynamical instabilities near the base of the jets, triggered by processes modulated by the magnetic field of the accretion disc. We present a qualitative treatment as the possible explanation for the observed large amplitude flux changes in both the source-intrinsic and source-extrinsic scenarios., Comment: 11 pages, 6 figures, MNRAS accepted

Full list of authors: Valtonen, Mauri J.; Dey, Lankeswar; Zola, S.; Ciprini, S.; Kidger, M.; Pursimo, T.; Gopakumar, A.; Matsumoto, K.; Sadakane, K.; Caton, D. B.; Nilsson, K.; Komossa, S.; Bagaglia, M.; Baransky, A.; Boumis, P.; Boyd, D.; Castro-Tirado, A. J.; Debski, B.; Drozdz, M.; Escartin Perez, A.; Fiorucci, M.; Garcia, F.; Gazeas, K.; Ghosh, S.; Godunova, V; Gomez, J. L.; Gredel, R.; Grupe, D.; Haislip, J. B.; Henning, T.; Hurst, G.; Janik, J.; Kouprianov, V. V.; Lehto, H.; Liakos, A.; Mathur, S.; Mugrauer, M.; Naves Nogues, R.; Nucciarelli, G.; Ogloza, W.; Ojha, D. K.; Pajdosz-Smierciak, U.; Pascolini, S.; Poyner, G.; Reichart, D. E.; Rizzi, N.; Roncella, F.; Sahu, D. K.; Sillanpaa, A.; Simon, A.; Siwak, M.; Soldan Alfaro, F. C.; Sonbas, E.; Tosti, G.; Vasylenko, V.; Webb, J. R.; Zielinski, P., OJ 287 is a BL Lacertae type quasar in which the active galactic nucleus (AGN) outshines the host galaxy by an order of magnitude. The only exception to this may be at minimum light when the AGN activity is so low that the host galaxy may make quite a considerable contribution to the photometric intensity of the source. Such a dip or a fade in the intensity of OJ 287 occurred in 2017 November, when its brightness was about 1.75 mag lower than the recent mean level. We compare the observations of this fade with similar fades in OJ 287 observed earlier in 1989, 1999, and 2010. It appears that there is a relatively strong reddening of the B− V colours of OJ 287 when its V-band brightness drops below magnitude 17. Similar changes are also seen in V− R, V− I, and R− I colours during these deep fades. These data support the conclusion that the total magnitude of the host galaxy is V = 18.0 ± 0.3, corresponding to MK = −26.5 ± 0.3 in the K-band. This is in agreement with the results, obtained using the integrated surface brightness method, from recent surface photometry of the host. These results should encourage us to use the colour separation method also in other host galaxies with strongly variable AGN. In the case of OJ 287, both the host galaxy and its central black hole are among the biggest known, and its position in the black hole mass–galaxy mass diagram lies close to the mean correlation. © 2022 The Author(s). Published by Oxford University Press on behalf of Royal Astronomical Society., SZ would also like to acknowledge support of the NCN grant no. 2018/29/B/ST9/01793, and KM JSPS KAKENHI grant no. 19K03930., With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709.

This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. Stellar occultations have become one of the best techniques to gather information about the physical properties of trans-Neptunian objects (TNOs), which are critical objects for understanding the origin and evolution of our Solar System. Aims. The purpose of this work is to determine, with better accuracy, the physical characteristics of the TNO (84922) 2003 VS2 through the analysis of the multichord stellar occultation on 2019 October 22 and photometric data collected afterward. Methods. We predicted, observed, and analyzed the multichord stellar occultation of the Second Gaia Data Release (Gaia DR2) source 3449076721168026624 (mυ = 14.1 mag) by the plutino object 2003 VS2 on 2019 October 22. We performed aperture photometry on the images collected and derived the times when the star disappeared and reappeared from the observing sites that reported a positive detection. We fit the extremities of such positive chords to an ellipse using a Monte Carlo method. We also carried out photometric observations to derive the rotational light curve amplitude and rotational phase of 2003 VS2 during the stellar occultation. Combining the results and assuming a triaxial shape, we derived the 3D shape of 2003 VS2. Results. Out of the 39 observatories involved in the observational campaign, 12 sites, located in Bulgaria (one), Romania (ten), and Serbia (one), reported a positive detection; this makes it one of the best observed stellar occultations by a TNO so far. Considering the rotational phase of 2003 VS2 during the stellar occultation and the rotational light curve amplitude derived (Am = 0.264 ± 0.017 mag), we obtained a mean area-equivalent diameter of DAeq = 545 ± 13 km and a geometric albedo of 0.134 ± 0.010. By combining the rotational light curve information with the stellar occultation results, we derived the best triaxial shape for 2003 VS2, which has semiaxes a = 339 ± 5 km, b = 235 ± 6 km, and c = 226 ± 8 km. The derived aspect angle of 2003 VS2 is θ = 59° ± 2° or its supplementary θ = 121° ± 2°, depending on the north-pole position of the TNO. The spherical-volume equivalent diameter is DVeq = 524 ± 7 km. If we consider large albedo patches on its surface, the semi-major axis of the ellipsoid could be ~ 10 km smaller. These results are compatible with the previous ones determined from the single-chord 2013 and four-chord 2014 stellar occultations and with the effective diameter and albedo derived from Herschel and Spitzer data. They provide evidence that 2003 VS2’s 3D shape is not compatible with a homogeneous triaxial body in hydrostatic equilibrium, but it might be a differentiated body and/or might be sustaining some stress. No secondary features related to rings or material orbiting around 2003 VS2 were detected. © M. Vara-Lubiano et al. 2022., We acknowledge financial support from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). Funding from Spanish projects PID2020-112789GB-I00 from AEI and Proyecto de Excelencia de la Junta de Andalucía PY20-01309 is acknowledged. Part of the research leading to these results has received funding from the European Research Council under the European Community’s H2020 (2014-2020/ERC Grant Agreement no. 669416 “LUCKY STAR”). M.V-L. acknowledges funding from Spanish project AYA2017-89637-R (FEDER/MICINN). P.S-S. acknowledges financial support by the Spanish grant AYA-RTI2018-098657-J-I00 “LEO-SBNAF”. Part of the work of M.P. was financed by a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS – UEFIS– CDI, PN-III-P1-1.1-TE-2019-1504. E.F.-V. acknowledges financial support from the Florida Space Institute and the Space Research Initiative. The following authors acknowledge the respective CNPq grants: F.B-R 309578/2017-5; B.E.M. 150612/2020-6; RV-M 304544/2017-5, 401903/2016-8; J.I.B.C. 308150/2016-3 and 305917/2019-6; M.A 427700/2018-3, 310683/2017-3 and 473002/2013-2. D.I. and O.V. acknowledge funding provided by the Ministry of Education, Science, and Technological Development of the Republic of Serbia (contracts 451-039/2021-14/200104, 451-03-9/2021-14/200002). D.I. acknowledges the support of the Alexander von Humboldt Foundation. M.H. thanks the Slovak Academy of Sciences (VEGA No. 2/0059/22) and the Slovak Research and Development Agency under the Contract No. APVV-19-0072. This work has also been supported by the VEGA grant of the Slovak Academy of Sciences No. 2/0031/18. A.P., R.S. and C.K. acknowledge the grant of K-138962 of National Research, Development and Innovation Office (Hungary). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and the National Institute of Science and Technology of the e-Universe project (INCT do e-Universo, CNPq grant 465376/2014-2). This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. This research is partially based on observations collected at the Centro Astronómico Hispano-Alemán (CAHA) at Calar Alto, operated jointly by Junta de Andalucía and Consejo Superior de Investigaciones Científicas (IAA-CSIC). This research is also partially based on observations carried out at the Observatorio de Sierra Nevada (OSN) operated by Instituto de Astrofísica de Andalucía (CSIC). This article is also based on observations made in the Observatorios de Canarias del IAC with the Liverpool Telescope operated on the island of La Palma by the Instituto de Astrofísica de Canarias in the Roque de los Muchachos Observatory.

SummarycAMP signaling pathways are critical for both oncogenesis and tumor suppression. cAMP signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. We developed a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncovered a previously unappreciated nuclear cAMP microdomain that functionally activates a tumor suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397, export of YAP from the nucleus, without YAP protein degradation. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer, and since Hippo pathway deregulation can lead to oncogenesis and chemotherapeutic resistance, drugs directed at the nuclear cAMP microdomain may provide new avenues for the treatment of cancer.

Cyclic AMP (cAMP) signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. Here, we present a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncover a nuclear cAMP microdomain that activates a tumor-suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397 and export of YAP from the nucleus with no change in YAP protein stability. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer; thus, drugs directed at the nuclear cAMP microdomain may provide avenues for the treatment of cancer.

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin

The nuclei of cells may exhibit invaginations of the nuclear envelope under a variety of conditions. These invaginations form a branched network termed the nucleoplasmic reticulum (NR), which may be found in cells in pathological and physiological conditions. While an extensive NR is a hallmark of cellular senescence and shows associations with some cancers, very little is known about the formation of NR in physiological conditions, despite the presence of extensive nuclear invaginations in some cell types such as endometrial cells. Here we show that in these cells the NR is formed in response to reproductive hormones. We demonstrate that oestrogen and progesterone are sufficient to induce NR formation and that this process is reversible without cell division upon removal of the hormonal stimulus. Nascent lamins and phospholipids are incorporated into the invaginations suggesting that there is a dedicated machinery for its formation. The induction of NR in endometrial cells offers a new model to study NR formation and function in physiological conditions.

The mammalian nuclear envelope (NE) can develop complex dynamic membrane-bounded invaginations in response to both physiological and pathological stimuli. Since the formation of these nucleoplasmic reticulum (NR) structures can occur during interphase, without mitotic NE breakdown and reassembly, some other mechanism must drive their development. Here we consider models for deformation of the interphase NE, together with the evidence for their potential roles in NR formation.

Cyclic AMP can both promote and suppress tumor growth; however, how this single second messenger can simultaneously have such disparate effects on cancer remains largely undefined. It is well appreciated that cAMP does not diffuse within a cell but is made in microdomains, which consist of a unique adenylyl cyclase, one or more phosphodiesterases, and cAMP effector proteins, but the role of specific cAMP microdomains in cancer is unclear. Examination of human tissue biopsies revealed that the nuclear cAMP microdomain, defined by the soluble adenylyl cyclase (sAC), is upregulated early in tumorigenesis, but is lost with melanoma invasion and metastasis. Further, we showed that loss of sAC led to the transformation of melanocytes and reintroduction of sAC, only into the nucleus, was sufficient to block tumorigenesis in vitro and in mice. Neither mitochondrial, nor cytoplasmic cAMP microdomains affected tumor cell growth. Activation of nuclear sAC led to significant changes in chromatin accessibility suggesting that this cAMP microdomain regulates numerous transcription factors. Specifically, activation of nuclear sAC led to reduced chromatin accessibility for the TEAD and SMAD family of transcription factors, the key effectors of the Hippo Pathway. Consistent with those data, nuclear sAC suppressed TEAD-dependent pro-cancer gene expression profiles (e.g., MYC) by inhibiting YAP, one of the main oncoproteins in this signaling cascade. Moreover, we showed that nuclear cAMP evokes the same YAP-dependent inhibition of the Hippo Pathway in a variety of cancers, suggesting tumor suppression by nuclear sAC is not limited to melanoma. These studies reveal that a cAMP microdomain wholly contained within the nucleus is a pivotal a tumor suppressor that acts via Hippo Pathway inactivation. Citation Format: Marek M. Drozdz, Ashley Doane, Garrett Desman, Jenny Wang, Michael Reilly, Kelsey Aguirre, Elsbeth Kane, Jedd Wolchok, Taha Merghoub, Olivier Elemento, Elena Piskounova, Jonathan Zippin. A nuclear cAMP microdomain suppresses tumor growth by Hippo Pathway inactivation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 287.

Aims: Iron deficiency (ID) is a common co-morbidity in heart failure (HF), associated with impaired functional capacity, poor quality of life and increased morbidity and mortality. Treatment with intravenous (i.v.) ferric carboxymaltose (FCM) has shown improvements in functional capacity, symptoms and quality of life in stable HF patients with reduced ejection fraction. The effect of i.v. iron supplementation on morbidity and mortality in patients hospitalised for acute HF (AHF) and who have ID has yet to be established. The objective of the present article is to present the rationale and design of the AFFIRM-AHF trial (ClinicalTrials.gov NCT02937454) which will investigate the effect of i.v. FCM (vs. placebo) on recurrent HF hospitalisations and cardiovascular (CV) mortality in iron-deficient patients hospitalised for AHF. Methods: AFFIRM-AHF is a multicentre, randomised (1:1), double-blind, placebo-controlled trial which recruited 1100 patients hospitalised for AHF and who had iron deficiency ID defined as serum ferritin

Nanoscale chemical mapping of newly-synthesised phospholipid molecules inside a mammalian cell is demonstrated using tip-enhanced Raman spectroscopy (TERS) for the first time using mouse pre-adipocyte cells as a model system. Newly-synthesised membrane phospholipid distribution within a pre-adipocyte cell is mapped with

Cyclic AMP (cAMP), a ubiquitous second messenger, has a broad impact on cellular processes such as proliferation, differentiation, apoptosis, migration, and gene expression. It has been widely linked to melanomagenesis; however, studies often report contradictory functions for cAMP (e.g., cancer promotion, but also tumor suppression and therapy resistance). Thus, a huge conundrum exists in the field of cAMP signaling and melanoma – one that might be explained by examining cAMP at the level of microdomains. In mammalian cells, two classes of adenylyl cyclases synthesize cAMP: the transmembrane adenylyl cyclases (tmACs) and the soluble adenylyl cyclase (sAC). Unlike tmACs, which are tethered to the plasma membrane, sAC is expressed throughout the cell and within organelles (e.g., nucleus and mitochondria). Thus, sAC and tmACs define distinct sources that generate cAMP in spatially separated cell regions, further restricted by the cAMP catabolizing enzymes phosphodiesterases (PDEs). Since cAMP signaling cascades can be evoked and restricted to small compartments, it is imperative that we interrogate all available cAMP microdomains to truly unravel their role in melanoma. To address this question, we have created a panel of virally-encoded, doxycycline-inducible sAC cDNAs, targeted to specific cellular compartments, i.e. nucleus, cytoplasm or mitochondria. We infected a melanoma sAC knock-out cell line with these cDNAs and have established single clone cell lines where sAC activity can be rapidly restored, only in a specific microdomain, at near pharmacologic time scales. Utilizing these model cell lines, we showed that only the nuclear sAC-dependent cAMP microdomain inhibits melanoma growth, both in vitro and in mice. Neither mitochondrial, nor cytoplasmic sAC cAMP microdomains affected tumor cell growth. Using ATACseq and RNAseq, we discovered that the nuclear cAMP microdomain leads to specific changes in chromatin landscape and a unique gene expression profile, distinct from the canonical MC1R/cAMP-dependent gene expression profile, that encompasses a range of genes with both established and potentially new roles in melanomagenesis. Immunohistochemical analysis of melanoma patient biopsies revealed that sAC localization in melanocytes is not static; while sAC is mostly cytoplasmic in benign melanocytes, it becomes nuclear as melanocytes undergo early malignant transformation (in situ disease and radial growth phase) but is lost from the nucleus upon transition to vertical growth phase. These data suggest that nuclear sAC expression is an early tumor suppressive pathway that is lost in melanoma cells capable of dermal invasion. Thus the pattern of cellular localization of sAC during different stages of melanoma may be a prognostic marker. Taken together, our findings support a novel tumor suppressor pathway that relies on the expression of sAC in specific cellular microdomains. Citation Format: Marek M. Drozdz, Jenny Wang, Michael Reilly, Elsbeth Kane, Kelsey Aguirre, Ashley Doane, Jedd D. Wolchok, Olivier Elemento, Garrett Desman, Taha Merghoub, Elena Piskounova, Jonathan Zippin. A nuclear cAMP microdomain functions as a tumor suppressor in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-081.

We present the results of our power spectral density analysis for the BL Lac object OJ\,287, utilizing the {\it Fermi}-LAT survey at high-energy $\gamma$-rays, {\it Swift}-XRT in X-rays, several ground-based telescopes and the {\it Kepler} satellite in the optical, and radio telescopes at GHz frequencies. The light curves are modeled in terms of continuous-time auto-regressive moving average (CARMA) processes. Owing to the inclusion of the {\it Kepler} data, we were able to construct \emph{for the first time} the optical variability power spectrum of a blazar without any gaps across $\sim6$ dex in temporal frequencies. Our analysis reveals that the radio power spectra are of a colored-noise type on timescales ranging from tens of years down to months, with no evidence for breaks or other spectral features. The overall optical power spectrum is also consistent with a colored noise on the variability timescales ranging from 117 years down to hours, with no hints of any quasi-periodic oscillations. The X-ray power spectrum resembles the radio and optical power spectra on the analogous timescales ranging from tens of years down to months. Finally, the $\gamma$-ray power spectrum is noticeably different from the radio, optical, and X-ray power spectra of the source: we have detected a characteristic relaxation timescale in the {\it Fermi}-LAT data, corresponding to $\sim 150$\,days, such that on timescales longer than this, the power spectrum is consistent with uncorrelated (white) noise, while on shorter variability timescales there is correlated (colored) noise., Comment: ApJ accepted

Human U1 small nuclear (sn)RNA, required for splicing of pre-mRNA, is encoded by genes on chromosome 1 (1p36). Imperfect copies of these U1 snRNA genes, also located on chromosome 1 (1q12-21), were thought to be pseudogenes. However, many of these “variant” (v)U1 snRNA genes produce fully processed transcripts. Using antisense oligonucleotides to block the activity of a specific vU1 snRNA in HeLa cells, we have identified global transcriptome changes following interrogation of the Affymetrix Human Exon ST 1.0 array. Our results indicate that this vU1 snRNA regulates expression of a subset of target genes at the level of pre-mRNA processing. This is the first indication that variant U1 snRNAs have a biological function in vivo. Furthermore, some vU1 snRNAs are packaged into unique ribonucleoproteins (RNPs), and many vU1 snRNA genes are differentially expressed in human embryonic stem cells (hESCs) and HeLa cells, suggesting developmental control of RNA processing through expression of different sets of vU1 snRNPs.

The mom gene of bacteriophage Mu encodes an enzyme that converts adenine to N(6)-(1-acetamido)-adenine in the phage DNA and thereby protects the viral genome from cleavage by a wide variety of restriction endonucleases. Mu-like prophage sequences present in Haemophilus influenzae Rd (FluMu), Neisseria meningitidis type A strain Z2491 (Pnme1) and H. influenzae biotype aegyptius ATCC 11116 do not possess a Mom-encoding gene. Instead, at the position occupied by mom in Mu they carry an unrelated gene that encodes a protein with homology to DNA adenine N(6)-methyltransferases (hin1523, nma1821, hia5, respectively). Products of the hin1523, hia5 and nma1821 genes modify adenine residues to N(6)-methyladenine, both in vitro and in vivo. All of these enzymes catalyzed extensive DNA methylation; most notably the Hia5 protein caused the methylation of 61% of the adenines in λ DNA. Kinetic analysis of oligonucleotide methylation suggests that all adenine residues in DNA, with the possible exception of poly(A)-tracts, constitute substrates for the Hia5 and Hin1523 enzymes. Their potential 'sequence specificity' could be summarized as AB or BA (where B = C, G or T). Plasmid DNA isolated from Escherichia coli cells overexpressing these novel DNA methyltransferases was resistant to cleavage by many restriction enzymes sensitive to adenine methylation.

Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the binary black hole model for OJ~287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the binary black hole central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole "no-hair theorem" at the 10% level., 24 pages, 11 figures, 3 tables, accepted for publication in ApJ

The use of an embedded waveguide to monitor the setting and early hardening of concrete has been investigated. The technique uses measurements of the attenuation of a guided wave propagating along the waveguide to obtain the shear velocity, and hence shear modulus, of the concrete. Tests have been carried out on mortar and concrete specimens monitored continuously over 48 hours. Over the first few hours, while the mortar/concrete was still fluid, the absolute rate of increase in shear modulus was low. From around 5 hours to around 20 hours, shear modulus increased linearly. Thereafter, shear modulus increased, but at an ever-decreasing rate. The shear velocity of the mortar was calculated to be 1720 m/s after two days, corresponding to a shear modulus of 5.6 GPa, while the 48 hour-old concrete had a shear modulus of 16.5 GPa. Repeated tests showed similar end states, but some differences in hardening rate; these were attributed either to temperature variations or to differences in mould geometry. The technique worked equally well on mortar and concrete, indicating that the presence of the large aggregate particles in concrete does not adversely affect the results.

Rational developments of energy systems of different scale (local, national or global) need a complex system of information. The author presents such a system, creating the principles of a virtual model of energy and environment at the regional scale. The information system consists of two basic subsystems—energy and environment. The system information should be supplied with a stream of data, from environmental monitoring. The main problems discussed in the article are renewable energy resources and their presentation in the information system. The author also presents the following: (1) influence of energy processes on the environment; (2) classification of the influence of waste on the environment; (3) the influence of products and technological processes on the environment; and (4) techniques of material waste elimination.

The Polish energy-system needs intensive investments in new technologies, which are energy efficient, clean and cost effective. Since the early 1990s, the Polish economy has had practically full access to modern technological devices, equipment and technologies. Introducing new technologies is a difficult task for project teams, constructors and investors. The author presents a set of principles for project teams useful in planning and energy modernisation. Several essential features are discussed: Energy-efficient appliances and systems; Choice of energy carriers, media and fuels; Optimal tariffs, maximum power and installed power; Intelligent, integrated, steering systems; Waste-energy recovery; Renewable-energy recovery. In practice there are several difficulties connected with planning and realising good technological and economic solutions. The author presents his own experiences of energy-system modernisation of industrial processes and building new objects.

A mathematical model of the behaviour of a geothermal-energy source, based on the theoretical water well of different quality parameters has been presented. Heat energy magnification produced by the well by increasing the stream of pumping water is analysed. Optimisation analyses are conducted assuming different types of source: constant or dynamic parameters. The technical optimisation model maximises the net power of the source, which is the difference between the heat source power and the power of pumping. The optimisation model maximises the value of heat energy produced by the source minus the value of the electrical energy used for pumping. The technical and economic optimisation gives different results because the unit cost of heat energy is lower than that of electrical energy.

Diagnostic and therapeutic strategies in boys with congenital posterior urethral valves (PUV) have much improved in past decades, but the impact of these changes on the progression to end-stage renal disease (ESRD) has rarely been investigated. We followed renal function in 20 boys with PUV from diagnosis to ESRD. From the first observation period (1969-1978) to the second period (1979-1992) we found a marked drop in age at diagnosis, at valve resection, at first increase of serum creatinine (SCr), and at onset of ESRD. The progression was analyzed by calculating the slope of 1/SCr and the probability of renal survival. In all patients combined, renal survival at the age of 10 years was 35%. In children undergoing valve resection in the 1st year of life, renal survival was worse than in those undergoing later surgery (15% vs. 65% after 10 years, P=0.006). Patients with a SCr1.2 mg/dl before the age of 12 months progressed more rapidly to ESRD than those attaining this level later. The lower the minimum level of SCr observed after initial surgery, the older the patient at the onset of ESRD. The presence of renal dysplasia or hypoplasia, but not of vesicoureteric reflux, was associated with a more rapid progression. Mean body height at ESRD was -2.3+/-1.3 standard deviation score compared with controls, and was lower if PUV was diagnosed before the age of 6 months.

OJ 287 is a BL Lac object at redshift.z= 0.306 that has shown double-peaked bursts at regular intervals of ∼12 yr during the last ∼40 yr. We analyse optical photopolarimetric monitoring data from 2005 to 2009, during which the latest double-peaked outburst occurred. The aim of this study is twofold: firstly, we aim to analyse variability patterns and statistical properties of the optical polarization light curve. We find a strong preferred position angle in optical polarization. The preferred position angle can be explained by separating the jet emission into two components: an optical polarization core and chaotic jet emission. The optical polarization core is stable on time-scales of years and can be explained as emission from an underlying quiescent jet component. The chaotic jet emission sometimes exhibits a circular movement in the Stokes plane. We find six such events, all on the time-scales of 10-20 d. We interpret these events as a shock front moving forwards and backwards in the jet, swiping through a helical magnetic field. Secondly, we use our data to assess different binary black hole models proposed to explain the regularly appearing double-peaked bursts in OJ 287. We compose a list of requirements a model has to fulfil to explain the mysterious behaviour observed in OJ 287. The list includes not only characteristics of the light curve but also other properties of OJ 287, such as the black hole mass and restrictions on accretion flow properties. We rate all existing models using this list and conclude that none of the models is able to explain all observations. We discuss possible new explanations and propose a new approach to understanding OJ 287. We suggest that both the double-peaked bursts and the evolution of the optical polarization position angle could be explained as a sign of resonant accretion of magnetic field lines, a 'magnetic breathing' of the disc. © 2010 The Authors. Journal compilation © 2010 RAS.

Doctor Bronisław Hager was born into the family of the Polish intelligentsia. He was brought up according to the Polish tradition with respect for freedom and independence. His father, Maxymilian was a fervent fighter in the struggle for independence of Silesia. His mother was involved in community service. Bronisław Hager finished his medical studies at Collegium Medicum of Jagiellonian University on 27th March 1914. Between World War I and World War II he actively fought for joining Silesia to Poland. During World War II he emigrated to London where he became one of members of the Polish government in exile. At the end of World War II he was a doctor of United Nations in Bavaria. He came back to the country on 22th November 1946. He settled in Tarnowskie Góry and worked at the community health center till 1967. He translated Sir Alexander Fleming's work on the discovery and using of penicillin. He died on 30th June 1969. Bronisław Hager was a good doctor, a great politician, a wonderful speaker and a real Pole.

A solution to the problem of improving the finite element (FE) modeling of elastic wave‐defect interaction is sought by reconsidering the conventional opinion on meshing strategy. The standard approach using uniform square elements imposes severe limitations in representing complex defect outlines but this is thought to improve when the mesh is made finer. Free meshing algorithms available widely in commercial packages of late can cope with difficult features well but they are thought to cause scattering by the irregular mesh itself. This paper examines whether the benefits offered by free meshing in representing defects better outweigh the inaccuracies due to mesh scattering. If using the standard mesh, the questions whether mesh refinement leads to improved results and whether a practical strategy can be constructed are considered.

Rolls‐Royce Marine and Imperial College, London are working together to develop a conformable phased array membrane probe for the inspection of components with complex surface geometry. This device will allow inspection of welded components without the need to remove the weld cap. To assess the performance of the membrane device it must be benchmarked against conventional inspection techniques. As an aid to inspection qualification (IQ) a range of advanced modelling techniques are also under investigation. This paper reports on the experimental results obtained form this benchmark testing and compares these results to simulated data.

This paper presents a method of modelling guided waves propagation with Finite Elements using frequency domain analysis and absorbing regions. These regions are placed at the extremities of the models and can absorb guided waves, thus avoiding reflections from the boundaries. Guidelines for efficient definition of these regions are discussed. Typical case studies are presented in order to validate the process. This method will benefit the modelling of large problems such as the interaction of guided waves with complex 3D defects in complex 3D structures.

The aim of the study was the microscopic evaluation of internal structure of cuprophane and polysulfone membrane and their surface analysis before and after reprocessing. The investigations were performed using an optical measurement system (Digital Instruments), a scanning electron microscope (SEM) and an atomic force microscope (AFM). We confirmed by SEM that reprocessing completely removed biofilm from both membranes surface. The analysis based on AFM visualized channels in the examined membrane. The diameter of the channels varied from 150 nm for cuprophane to 380 nm for polysulfone. The roughness expressed as root mean square (RMS) was higher for cuprophane than for polysulfone membrane. The physical differences between nanostrucure of the examined membranes might be responsible for lower biocompatibility of cuprophane.

The aim of a study was to estimate the renal osteodystrophy status using bone densitometry in relation to selected biochemical parameters of calcium-phosphate metabolism. The study population consisted of 123 patients with end-stage renal disease, including 24 patients treated with continuous ambulatory peritoneal dialysis (CAPD), aged between 22 and 73 years (mean 49.9 years), on dialysis program for mean period of 14.9 months and 99 patients on maintenance hemodialysis for mean period of 58.8 months, aged between 19 and 72 years (mean 46.6 years). Densitometric measurements using DEXA technique were performed in three different skeletal points: distal ends of both radial bones, lumbar spinal region and femoral neck. Concomitantly, serum concentrations of total and ionized calcium, phosphates and parathormone as well as alkaline phosphatase serum activity were measured. Among male patients treated with CAPD significantly higher BMD values in right forearm were found as compared to women treated with this method (0.769 vs. 0.616; p0.001). Higher values of BMD were also found in both forearms in whole CAPD population as compared to those on hemodialysis. However, there was no difference in densitometry results between CAPD and HD patients as well as between men and women within these groups, when measured in femoral neck and lumbar spinal region. Among hemodialysis patients higher levels of phosphates and PTH were found as compared to CAPD, doses of drugs used for treatment of osteodystrophy--calcium carbonate, aluminum hydroxide and active vitamin D were also higher in individuals on HD. In addition, in CAPD patients statistically significant, positive correlations were found between BMD value in lumbar spinal area as well as in femoral neck and amount of ingested calcium carbonate, between BMD in lumbar spinal area and aluminum hydroxide dose taken by patients and between BMD in both forearms and dose of active vitamin D. We failed to demonstrate any relationship between obtained densitometric results as well as biochemical markers of calcium-phosphate metabolism and quantitative parameters of dialysis adequacy in both treatment modes. Obtained results let us to conclude that renal osteodystrophy is less advanced in patients treated with peritoneal dialysis, however this may be related only to markedly shorter renal replacement therapy period in this group. Lack of significant abnormalities in densitometry measurements taken in lumbar spinal area and femoral neck, while they are present in forearms, may suggest that the latter point of skeleton may be most useful for identification of bone mass deficiency in dialyzed patients.

The aim of this study was to evaluate if there were any differences in clinical outcome as well as in values of quantitative adequacy/nutritional parameters in ESRD patients treated with continuous ambulatory peritoneal dialysis, depending on their sex. Nutritional and adequacy parameters: NPCR, Kt/V, weekly creatinine clearance (wClCr), dialysis index (DI), serum albumin concentration, as well as clinical parameters such as hospitalization rate, admission rate, peritonitis rate, exit-site infection rate and co-morbidity score were evaluated in 31 CAPD patients (12 F and 19 M). Lower comorbidity score (0.583 vs. 1.58 points; p0.05) and higher Kt/V total and residual (2.25 vs. 1.57; p0.01 and 1.7 vs. 1.42; p0.01, respectively) were found in women as compared to men. The value of the quantitative nutritional parameter--NPCR--was also higher in women (0.842 vs. 0.73 g/kg b.w./24 hours; p0.05). Despite these differences, only a small difference was found in the clinical outcome and survival between men and women. The obtained data may suggest that women can achieve better treatment results with the CAPD method as compared to men.

A new mutational basis for human disease was discovered in the beginning of this decade. The genes responsible for fragile X syndrome, spinobulbar muscular atrophy and later the genes causing myotonic dystrophy and Huntington disease were shown to harbor unstable, expanding trinucleotide repeats. The dynamic nature of these mutations explained intriguing features of clinical symptoms observed in families inheriting these diseases. The increasing disease penetrance and expresivity in subsequent family generations could be correlated with the increasing number of trinucleotide repeats. Now, thirteen human hereditary neurological diseases are known to have their underlying cause in the trinucleotide repeat expansions [1] and their list is likely to grow.

Malnutrition is a serious and common problem among patients dialyzed with peritoneal dialysis. Simple and reproducible methods of nutritional status assessment are needed for early problem identification to prevent and treat this complication. The aim of the present study was to evaluate the usefulness of albumin serum concentration and normalized protein catabolic rate (NPCR) derived from urea kinetic modeling session to assess the clinical status of ESRD patients treated with Continuous Ambulatory Peritoneal Dialysis (CAPD). Statistically significant, negative correlations between NPCR and hospitalization rate (r = -0.307; p0.05) and co-morbidity score (r = -0.429; p0.001) as well as statistically higher NPCR in the group of patients who survived the whole study period (0.82 vs. 0.74 in Non-Survivors; p0.01) support the value of this marker as an indicator of clinical status of peritoneal dialysis patients. Significant, negative correlations between serum albumin level and co-morbidity score (r = -0.379; p0.05), peritonitis rate (r = -0.359; p0.05) and hospitalization rate (r = -0.601; p0.005) were also found. Low absolute values of NPCR for the whole population as well as significant, positive correlations of this marker with dialysis adequacy parameters with concomitant lack of such correlations for albumin indicate, that NPCR as a nutritional marker should be interpreted with caution, and always regarded to the calculation method.

The purpose of the experiment was to evaluate the metabolism of the connective tissue (collagen and proteoglycans) in the endothelial cell culture (enzymatically isolated from porcine aortas). The endothelial cells were activated by 1-10 ng/ml TGF-beta 1 and 250 pg/ml IL-1 beta together and separately. Intensity of proteoglycan synthesis has been evaluated by using radioactive [35S]-sodium sulfate whereas the intensity of collagen was evaluated by incorporation of [3H]-proline. The following conclusions have been drawn as the result of the experiment: 1) TGF-beta 1 stimulates the synthesis of proteoglycans and collagen in endothelial cell culture, whereas IL-1 beta has the opposite action; and 2) TGF-beta 1 reduces IL-1 beta action which hampers the synthesis of proteoglycans and collagen, provided that the culture's preincubation with TGF-beta 1 precedes the incubation with IL-1 beta.

The aim of the study was to evaluate the influence of follow fiber dialyzers reprocessing procedure on urea kinetic modeling parameters, dialysis effectiveness for small molecules and effective clearance/predicted clearance ratio. Fifty patients (27 F, 23 M) aged 18-61 years (mean 47) being on maintenance hemodialysis due to end stage renal failure for 4-136 months were included into the study. Patients were treated 3 times a week with blood flow 160-290 ml/min and dialysate flow 500 ml/min. The dialysis time was calculated individually based on urea kinetic modeling parameters. Reprocessing of dialyzers was performed using Renatron RS 8300 and Renalin as sterilized agent. Dialysers with ppr below 80% were excluded from the use. Mean values of dialysis index Kt/V, TAC and dialysis effectiveness (Ct/C0) for urea, creatinine, uric acid and kalium as well as values of effective/predicted clearance ratio for consecutive reprocessing procedures were compared with the results obtained for the new dialyzers. There was no significant influence of reprocessing procedure on Kt/V, TAC and Ct/C0 for tested substances and studied clearances. The obtained results indicates that dialysers reprocessing procedure performed according to the described protocol was safe and didn't decrease dialysis effectiveness.

This study is the preliminary review of the above 2 year period of treatment of patients with chronic renal failure being on CAPD in our center. The study was performed in 14 patients during the cumulative period of 192 patient-months. The analysis of infectious and non-infectious complications was conducted, and patients were also monitored in terms of quantitive measurements of dialysis adequacy and nutritional status using such parameters like total Kt/V (urea), total Weekly Creatinine Clearance (tWCC), normalized protein catabolic rate (npcr) and serum albumin level. We also analysed the influence of residual renal function (RRF) on these parameters and relationships between them. During the study period we observed 7 episodes of peritonitis with the medium rate of 1 episode per 24.7 patient-months. Six of them were treated succesfully conservatively, but in one case catheter removal was necessary because of uneffective farmacological therapy. We also observed two episodes of exist site infection (ESI), one treated finally by catheter replacement. Two technical problems also occurred: leakage into abdominal wall and through the catheter tunnel. During the observation period all patients remained alive, although one was transfered to HD after 14 months of CAPD (earlier 4 months on manual IPD) because of lack of adequacy and severe peritonitis. Obtained results of nutritional status indicate, that 50% of patients were malnourished in terms of npcr and 35.7% in terms of serum albumin level. Seven of 14 patients were adequately dialysed acording to Kt/V, 9 according to tWCC.

The effect of urea kinetic modeling (u.k.m.) application on dialysis efficiency and metabolic status was evaluated in 50 maintenance dialyzed patients. U.k.m. sessions were performed once a month based on the self-developed computer program to control dialysis. The dialysis index (Kt/V), the time averaged concentration (TAC), protein catabolic rate (pcr) and dialysis effectiveness (Ct/Co) were evaluated and the results obtained at the beginning and after 2, 4, and 8 months of the study were compared. Kt/V had risen significantly in the modeled patients from 1.04 to 1.24 and was accompanied by 12% Ct/Co increase of urea removal after 8 months. The tendency of the moderate (non significant) decrease of TAC from 54.57 to 52.48 mg% BUN was observed during the study. According to the NCDS criteria the percentage of adequately dialyzed patients increased from 42% at the beginning to 64% after 80 months; underdialyzed patients decreased from 16% to 6% and malnourished also from 16% to 6%, respectively, after u.k.m. application. Dialysis effectiveness for creatinine and uric acid described by Ct/Co for the above after 4 and 8 months was significantly increased when compared with the results obtained at the beginning of the study. These results indicate that u.k.m. application allowed to take control over uremic toxemia and improved dialysis adequacy in patients on maintenance dialysis. Protein catabolic rate in studied patients increased from 1.18 to 1.24 g/kg/per day during the study and it was accompanied by a total blood protein and serum albumin increase. This could indicate improvement of the nutritional status of dialyzed subjects.

The effect of recombinant human erythropoietin (rHu-EPO) on anaemia and some biochemical parameters was investigated in 7 predialysis patients. A statistically significant increase in erythrocyte, haematocrit and haemoglobin levels was observed after 3 weeks of treatment and such changes were constant during the 6 month maintenance therapy. The mean urea and creatinine levels were comparable during the tested period in 4 of the studied patients. The other 3 patients did not completed the planed period and started the dialytic therapy because of progression of renal insufficiency. The latter group had more advanced renal failure and higher blood pressure prior to rHu-EPO treatment as compared with the patients who completed the study.