Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density

AbstractA novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity

THE RATE OF BINARY BLACK HOLE MERGERS INFERRED FROM ADVANCED LIGO OBSERVATIONS SURROUNDING GW150914

A transient gravitational-wave signal, GW150914, was identi fi ed in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To asse ss the implications of this discovery, the detectors remained in operation with unchanged con fi gurations over a period of 39 days around the time of t he signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate ( FAR ) of < ́ -- 4.9 10 yr 61 , yielding a p -value for GW150914 of < ́ - 210 7 . Parameter estimation follo w-up on this trigger identi fi es its source as a binary black hole ( BBH ) merger with component masses ( )( ) = - + - + mm M ,36,29 12 4 5 4 4 at redshift = - + z 0.09 0.04 0.03 ( median and 90% credible range ) . Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between – -- 2 53 Gpc yr 31 ( comoving frame ) . Incorporating all search triggers that pass a much lower threshold while accounting for the uncerta inty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from – -- 13 600 Gpc yr 31 depending on assumptions about the BBH mass distribution. All together, our various rate estimat es fall in the conservative range – -- 2 600 Gpc yr 31

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Infinitary rewriting: meta-theory and convergence

When infinitary rewriting was introduced by Kaplan et.al. at the beginning of the 1990s, its term universe was explained as the metric completion of a metric on finite terms. The motivation for this connection to topology was that it allowed to import other well-studied notions from metric spaces, in particular the notion of convergence as a replacement for normalisation. This paper generalises the approach by parameterising it with a term metric, and applying the process of metric completion not only to terms but also to operations on and relations between terms. The resulting meta-theory is studied, leading to a revised notion of infinitary rewrite system. For these systems a method is devised to prove their convergence

The essential roles of cytidine diphosphate-diacylglycerol synthase in bloodstream form Trypanosoma brucei

Funded by Wellcome Trust: Senior Research Fellowship, Grant Number: 067441 and Wellcome Trust, Grant Numbers: 082596, 093228.Lipid metabolism in Trypanosoma brucei, the causative agent of African sleeping sickness, differs from its human host in several fundamental ways. This has lead to the validation of a plethora of novel drug targets, giving hope of novel chemical intervention against this neglected disease. Cytidine diphosphate diacylglycerol (CDP-DAG) is a central lipid intermediate for several pathways in both prokaryotes and eukaryotes, being produced by CDP-DAG synthase (CDS). However, nothing is known about the single T. brucei CDS gene (Tb927.7.220/ EC 2.7.7.41) or its activity. In this study we show TbCDS is functional by complementation of a non-viable yeast CDS null strain and that it is essential in the bloodstream form of the parasite via a conditional knockout. The TbCDS conditional knockout showed morphological changes including a cell-cycle arrest due in part to kinetoplast segregation defects.Biochemical phenotyping of TbCDS conditional knockout showed drastically altered lipid metabolism where reducing levels of phosphatidylinositol detrimentally impacted on glycoylphosphatidylinositol biosynthesis. These studies also suggest that phosphatidylglycerol synthesised via the phosphatidylglycerol-phosphate synthase is not synthesised from CDP-DAG, as was previously thought. TbCDS was shown to localised the ER and Golgi, probably to provide CDP-DAG for the phosphatidylinositol synthases.Publisher PDFPeer reviewe

Impact of enhanced recovery on oncological outcomes following minimally invasive surgery for rectal cancer.

Oncological outcomes of locally advanced rectal cancer depend on the quality of surgical and oncological management. Enhanced recovery pathways (ERPs) have yet to be assessed for their oncological impact when used in combination with minimally invasive surgery. This study assessed outcomes with or without an ERP in patients with rectal cancer. This was a retrospective analysis of all consecutive adult patients who underwent elective minimally invasive surgery for primary rectal adenocarcinoma with curative intent between February 2005 and April 2018. Both laparoscopic and robotic procedures were included. Short-term morbidity and overall survival were compared between patients treated according to the institutional ERP and those who received conventional care. A total of 600 patients underwent minimally invasive surgery, of whom 320 (53·3 per cent) were treated according to the ERP and 280 (46·7 per cent) received conventional care. ERP was associated with less overall morbidity (34·7 versus 54·3 per cent; P &lt; 0·001). Patients in the ERP group had improved overall survival on univariable (91·4 versus 81·7 per cent at 5 years; hazard ratio (HR) 0·53, 95 per cent c.i. 0·28 to 0·99) but not multivariable (HR 0·78, 0·41 to 1·50) analysis. Multivariable analysis revealed age (HR 1·46, 1·17 to 1·82), male sex (HR 1·98, 1·05 to 3·70) and complications (HR 2·23, 1·30 to 3·83) as independent risk factors for compromised overall survival. Disease-free survival was comparable for patients who had ERP or conventional treatment (80·5 versus 84·6 per cent at 5 years respectively; P = 0·272). Treatment within an ERP was associated with a lower morbidity risk that may have had a subtle impact on overall but not disease-specific survival

Retention of inherited Ar by alkali fedspar xenocrysts in a magma: Kinetic constraints from Ba zoning profiles

40Ar/39Ar dating of volcanic alkali feldspars provides critical age constraints on many geological phenomena. A key assumption is that alkali feldspar phenocrysts in magmas contain no initial radiogenic 40Ar (40Ar*), and begin to accumulate 40Ar* only after eruption. This assumption is shown to fail dramatically in the case of a phonolitic lava from southern Tanzania that contains partially resorbed xenocrystic cores which host inherited 40Ar manifest in 40Ar/39Ar age spectra. Magmatic overgrowths on the xenocrysts display variable oscillatory zoning with pisodic pulses of Ba enrichment and intervals of resorption. Ba concentration profiles across contrasting compositional zones are interpreted as diffusion couples. Inferred temperature time histories recorded by these profiles reveal significant variations between phenocrysts. Combined with Ar diffusion kinetics for alkali feldspars and magma temperature inferred from two feldspar thermometry, the results indicate that >1% inherited 40Ar can be retained in such xenocrysts despite immersion in magma at ~900°C for tens to >100 years. In cases where the age contrast between inherited and magmatic feldspars is less pronounced, the age biasing effect of incompletely degassed xenocrysts may easily go undetected