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Summary Background: Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation). Methods: To determine if B4GALNT3 is the causal gene, B4galnt3−/− mice were developed and serum levels of total sclerostin and LDN-glycosylated sclerostin were analysed and mechanistic studies were performed in osteoblast-like cells. Mendelian randomization was used to determine causal associations. Findings: B4galnt3−/− mice had higher circulating sclerostin levels, establishing B4GALNT3 as a causal gene for circulating sclerostin levels, and lower bone mass. However, serum levels of LDN-glycosylated sclerostin were lower in B4galnt3−/− mice. B4galnt3 and Sost were co-expressed in osteoblast-lineage cells. Overexpression of B4GALNT3 increased while silencing of B4GALNT3 decreased the levels of LDN-glycosylated sclerostin in osteoblast-like cells. Mendelian randomization demonstrated that higher circulating sclerostin levels, genetically predicted by variants in the B4GALNT3 gene, were causally associated with lower BMD and higher risk of fractures but not with higher risk of myocardial infarction or stroke. Glucocorticoid treatment reduced B4galnt3−/− expression in bone and increased circulating sclerostin levels and this may contribute to the observed glucocorticoid-induced bone loss. Interpretation: B4GALNT3 is a key factor for bone physiology via regulation of LDN-glycosylation of sclerostin. We propose that B4GALNT3-mediated LDN-glycosylation of sclerostin may be a bone-specific osteoporosis target, separating the anti-fracture effect of global sclerostin inhibition, from indicated cardiovascular side effects.

Das frühneuzeitliche Europa ist gekennzeichnet durch eine enorme Zunahme von Mobilität, bedingt durch bessere Verkehrswege und technische Neuerungen seit dem Ausgang des Mittelalters. Religion konnte sich einerseits hemmend auf solche Mobilitätsprozesse auswirken. Andererseits konnten religiöse Beweggründe raumbezogene Mobilität aber auch befördern, ja zum Teil überhaupt erst bewirken. So löste die konfessionelle Spaltung der lateinischen Christenheit und die nachfolgende Konfessionalisierung in den Territorien Migrationsprozesse bisher ungekannter Größe aus, bis hin zur Auswanderung ganzer Glaubensgemeinschaften nach Übersee.Aber auch wirtschaftliche Zwänge, Kriege und Hungersnöte, die Ausübung von Handel und bestimmten Gewerben oder die akademische Ausbildung sowie die adelige Standeserziehung konnten Menschen gleich welchen religiösen Bekenntnisses dazu veranlassen, dauerhaft oder zeitweilig ihren Aufenthaltsort zu wechseln.Beide Phänomene, Religion und Mobilität, sind von der historischen Forschung bislang zumeist getrennt voneinander behandelt worden. Die Konfessionalisierungsforschung hat Religion bislang als Impulsgeber für Mobilität wahrgenommen und dabei den Zusammenhang mit anderen Formen von Mobilität zum Teil vernachlässigt. Die Beiträge des Bandes tragen dazu bei, religions- und migrationsgeschichtliche Ansätze und Fragestellungen zusammenzuführen und enger miteinander zu verzahnen. Im Mittelpunkt steht die Frage nach dem Stellenwert von Mobilität für die Ausbildung oder Auflösung religiös-konfessioneller Identitäten im frühneuzeitlichen Europa.

Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, whereas estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2-creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.

Several recent investigations indicate the existence of gender-related systematic trends in the peer review of proposals for observations on astronomical facilities. This includes the National Radio Astronomy Observatory (NRAO) where there is evidence of a gender imbalance in the rank of proposals with male principal investigators (PIs) favored over female PIs. Since semester 2017A (17A), the NRAO has taken the following steps: (1) inform science review panels (SRPs) and the telescope time allocation committee (TAC) about the gender imbalance; and (2) increase the female representation on SRPs and the TAC to reflect the community demographics. Here we analyze SRP normalized rank-ordered scores, or linear ranks, by PI gender for NRAO observing proposals from semesters 12A-21A. We use bootstrap resampling to generate modeled distributions and the Anderson-Darling (AD) test to evaluate the probability that the linear rank distributions for male and female PIs are drawn from the same parent sample. We find that between semesters 12A-17A that male PIs are favored over female PIs (AD p-value 0.0084), whereas between semesters 17B-21A female PIs are favored over male PIs, but at a lower significance (AD p-value 0.11). Therefore the gender imbalance is currently being ameliorated, but this imbalance may have been reversed. Regardless, we plan to adopt a dual-anonymous approach to proposal review to reduce the possibility of bias to occur., Comment: Accepted for publication in the PASP

With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.

Obesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (− 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on nonvertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1-expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur but no change in trabecular bone volume fraction in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared with control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce nonvertebral fracture risk.

Several recent investigations indicate the existence of gender-related systematic trends in the peer review of proposals for observations on astronomical facilities. This includes the National Radio Astronomy Observatory (NRAO) where there is evidence of a gender imbalance in the rank of proposals with male principal investigators (PIs) favored over female PIs. Since semester 2017A (17A), the NRAO has taken the following steps: (1) inform science review panels (SRPs) and the telescope time allocation committee (TAC) about the gender imbalance; and (2) increase the female representation on SRPs and the TAC to reflect the community demographics. Here we analyze SRP normalized rank-ordered scores, or linear ranks, by PI gender for NRAO observing proposals from semesters 12A-21A. We use bootstrap resampling to generate modeled distributions and the Anderson-Darling (AD) test to evaluate the probability that the linear rank distributions for male and female PIs are drawn from the same parent sample. We find that between semesters 12A-17A that male PIs are favored over female PIs (AD p-value 0.0084), whereas between semesters 17B-21A female PIs are favored over male PIs, but at a lower significance (AD p-value 0.11). Therefore the gender imbalance is currently being ameliorated, but this imbalance may have been reversed. Regardless, we plan to adopt a dual-anonymous approach to proposal review to reduce the possibility of bias to occur., Comment: Accepted for publication in the PASP

The Widefield ASKAP L-band Legacy All-sky Blind surveY (WALLABY) is a next-generation survey of neutral hydrogen (HI) in the Local Universe. It uses the widefield, high-resolution capability of the Australian Square Kilometer Array Pathfinder (ASKAP), a radio interferometer consisting of 36 x 12-m dishes equipped with Phased-Array Feeds (PAFs), located in an extremely radio-quiet zone in Western Australia. WALLABY aims to survey three-quarters of the sky (-90 degr < Dec < +30 degr) to a redshift of z < 0.26, and generate spectral line image cubes at ~30 arcsec resolution and ~1.6 mJy/beam per 4 km/s channel sensitivity. ASKAP's instantaneous field of view at 1.4 GHz, delivered by the PAF's 36 beams, is about 30 sq deg. At an integrated signal-to-noise ratio of five, WALLABY is expected to detect over half a million galaxies with a mean redshift of z ~ 0.05 (~200 Mpc). The scientific goals of WALLABY include: (a) a census of gas-rich galaxies in the vicinity of the Local Group; (b) a study of the HI properties of galaxies, groups and clusters, in particular the influence of the environment on galaxy evolution; and (c) the refinement of cosmological parameters using the spatial and redshift distribution of low-bias gas-rich galaxies. For context we provide an overview of previous large-scale HI surveys. Combined with existing and new multi-wavelength sky surveys, WALLABY will enable an exciting new generation of panchromatic studies of the Local Universe. - First results from the WALLABY pilot survey are revealed, with initial data products publicly available in the CSIRO ASKAP Science Data Archive (CASDA)., Comment: Accepted for publication in ApSS (38 pages, 14 figures), see also https://www.atnf.csiro.au/research/WALLABY/ - Contact email: Baerbel.Koribalski@csiro.au

The Widefield ASKAP L-band Legacy All-sky Blind surveY (WALLABY) is a next-generation survey of neutral hydrogen (HI) in the Local Universe. It uses the widefield, high-resolution capability of the Australian Square Kilometer Array Pathfinder (ASKAP), a radio interferometer consisting of 36 x 12-m dishes equipped with Phased-Array Feeds (PAFs), located in an extremely radio-quiet zone in Western Australia. WALLABY aims to survey three-quarters of the sky (-90 degr < Dec < +30 degr) to a redshift of z < 0.26, and generate spectral line image cubes at ~30 arcsec resolution and ~1.6 mJy/beam per 4 km/s channel sensitivity. ASKAP's instantaneous field of view at 1.4 GHz, delivered by the PAF's 36 beams, is about 30 sq deg. At an integrated signal-to-noise ratio of five, WALLABY is expected to detect over half a million galaxies with a mean redshift of z ~ 0.05 (~200 Mpc). The scientific goals of WALLABY include: (a) a census of gas-rich galaxies in the vicinity of the Local Group; (b) a study of the HI properties of galaxies, groups and clusters, in particular the influence of the environment on galaxy evolution; and (c) the refinement of cosmological parameters using the spatial and redshift distribution of low-bias gas-rich galaxies. For context we provide an overview of previous large-scale HI surveys. Combined with existing and new multi-wavelength sky surveys, WALLABY will enable an exciting new generation of panchromatic studies of the Local Universe. - First results from the WALLABY pilot survey are revealed, with initial data products publicly available in the CSIRO ASKAP Science Data Archive (CASDA)., Comment: Accepted for publication in ApSS (38 pages, 14 figures), see also https://www.atnf.csiro.au/research/WALLABY/ - Contact email: Baerbel.Koribalski@csiro.au

The Widefield ASKAP L-band Legacy All-sky Blind surveY (wallaby) is a next-generation survey of neutral hydrogen (Hi) in the Local Universe. It uses the widefield, high-resolution capability of the Australian Square Kilometer Array Pathfinder (ASKAP), a radio interferometer consisting of 36x12-m dishes equipped with Phased-Array Feeds (PAFs), located in an extremely radio-quiet zone in Western Australia. wallaby aims to survey three-quarters of the sky (-90 degrees

Previous studies evaluating the role of the androgen receptor (AR) for bone mass have used mouse models with global or tissue-specific lifelong inactivation of the AR. However, these mouse models have the AR inactivated already early in life and the relative roles of the AR during development, sexual maturation and in adult mice cannot be evaluated separately. The aim of the present study was to determine the specific roles of the AR in bone during sexual maturation and in adult mice. The AR was conditionally ablated at four (pre-pubertal) or ten (post-pubertal) weeks of age in male mice using tamoxifen-inducible Cre-mediated recombination. Both the pre-pubertal and the post-pubertal AR inactivation were efficient demonstrated by substantially lower AR mRNA levels in seminal vesicle, bone and white adipose tissue as well as markedly reduced weights of reproductive tissues when comparing inducible ARKO mice and control mice at 14 weeks of age. Total body BMD, as analyzed by DXA, as well as tibia diaphyseal cortical bone thickness and proximal metaphyseal trabecular bone volume fraction, as analyzed by μCT, were significantly reduced by both pre-pubertal and post-pubertal AR inactivation. These bone effects were associated with an increased bone turnover, indicating a high bone turnover osteoporosis. Pre-pubertal but not post-pubertal AR inactivation resulted in substantially increased fat mass. In conclusion, the AR is required for maintenance of both trabecular and cortical bone in adult male mice while AR expression during puberty is crucial for normal fat mass homeostasis in adult male mice.

Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Movérare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tucker

Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless‐type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell‐specific, and inducible Notum‐inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage–specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large‐scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast‐derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast‐derived NOTUM may prevent nonvertebral fractures.

There is a growing acknowledgement in the scientific community of the importance of making experimental data machine findable, accessible, interoperable, and reusable (FAIR). Recognizing that high quality metadata are essential to make datasets FAIR, members of the GO FAIR Initiative and the Research Data Alliance (RDA) have initiated a series of workshops to encourage the creation of Metadata for Machines (M4M), enabling any self-identified stakeholder to define and promote the reuse of standardized, comprehensive machine-actionable metadata. The funders of scientific research recognize that they have an important role to play in ensuring that experimental results are FAIR, and that high quality metadata and careful planning for FAIR data stewardship are central to these goals. We describe the outcome of a recent M4M workshop that has led to a pilot programme involving two national science funders, the Health Research Board of Ireland (HRB) and the Netherlands Organisation for Health Research and Development (ZonMW). These funding organizations will explore new technologies to define at the time that a request for proposals is issued the minimal set of machine-actionable metadata that they would like investigators to use to annotate their datasets, to enable investigators to create such metadata to help make their data FAIR, and to develop data-stewardship plans that ensure that experimental data will be managed appropriately abiding by the FAIR principles. The FAIR Funders design envisions a data-management workflow having seven essential stages, where solution providers are openly invited to participate. The initial pilot programme will launch using existing computer-based tools of those who attended the M4M Workshop.

There is a growing acknowledgement in the scientific community of the importance of making experimental data machine findable, accessible, interoperable, and reusable (FAIR). Recognizing that high quality metadata are essential to make datasets FAIR, members of the GO FAIR Initiative and the Research Data Alliance (RDA) have initiated a series of workshops to encourage the creation of Metadata for Machines (M4M), enabling any self-identified stakeholder to define and promote the reuse of standardized, comprehensive machine-actionable metadata. The funders of scientific research recognize that they have an important role to play in ensuring that experimental results are FAIR, and that high quality metadata and careful planning for FAIR data stewardship are central to these goals. We describe the outcome of a recent M4M workshop that has led to a pilot programme involving two national science funders, the Health Research Board of Ireland (HRB) and the Netherlands Organisation for Health Research and Development (ZonMW). These funding organizations will explore new technologies to define at the time that a request for proposals is issued the minimal set of machine-actionable metadata that they would like investigators to use to annotate their datasets, to enable investigators to create such metadata to help make their data FAIR, and to develop data-stewardship plans that ensure that experimental data will be managed appropriately abiding by the FAIR principles. The FAIR Funders design envisions a data-management workflow having seven essential stages, where solution providers are openly invited to participate. The initial pilot programme will launch using existing computer-based tools of those who attended the M4M Workshop., Comment: This is a pre-print of the FAIR Funders pilot, an outcome of the first Metadata for Machines workshop, see: https://www.go-fair.org/resources/go-fair-workshop-series/metadata-for-machines-workshops/. Corresponding author: E. A Schultes, ORCID 0000-0001-8888-635X

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.

MHONGOOSE is a deep survey of the neutral hydrogen distribution in a representative sample of 30 nearby disk and dwarf galaxies with HI masses from 10^6 to ~10^{11} M_sun, and luminosities from M_R ~ -12 to M_R ~ -22. The sample is selected to uniformly cover the available range in log(M_HI). Our extremely deep observations, down to HI column density limits of well below 10^{18} cm^{-2} - or a few hundred times fainter than the typical HI disks in galaxies - will directly detect the effects of cold accretion from the intergalactic medium and the links with the cosmic web. These observations will be the first ever to probe the very low-column density neutral gas in galaxies at these high resolutions. Combination with data at other wavelengths, most of it already available, will enable accurate modelling of the properties and evolution of the mass components in these galaxies and link these with the effects of environment, dark matter distribution, and other fundamental properties such as halo mass and angular momentum. MHONGOOSE can already start addressing some of the SKA-1 science goals and will provide a comprehensive inventory of the processes driving the transformation and evolution of galaxies in the nearby universe at high resolution and over 5 orders of magnitude in column density. It will be a Nearby Galaxies Legacy Survey that will be unsurpassed until the advent of the SKA, and can serve as a highly visible, lasting statement of MeerKAT's capabilities., Comment: To be published in "MeerKAT Science: On the Pathway to the SKA". Proceedings of Science. Workshop held 25-27 May, 2016 Stellenbosch, South Africa

MHONGOOSE is a deep survey of the neutral hydrogen distribution in a representative sample of 30 nearby disk and dwarf galaxies with HI masses from 10^6 to ~10^{11} M_sun, and luminosities from M_R ~ -12 to M_R ~ -22. The sample is selected to uniformly cover the available range in log(M_HI). Our extremely deep observations, down to HI column density limits of well below 10^{18} cm^{-2} - or a few hundred times fainter than the typical HI disks in galaxies - will directly detect the effects of cold accretion from the intergalactic medium and the links with the cosmic web. These observations will be the first ever to probe the very low-column density neutral gas in galaxies at these high resolutions. Combination with data at other wavelengths, most of it already available, will enable accurate modelling of the properties and evolution of the mass components in these galaxies and link these with the effects of environment, dark matter distribution, and other fundamental properties such as halo mass and angular momentum. MHONGOOSE can already start addressing some of the SKA-1 science goals and will provide a comprehensive inventory of the processes driving the transformation and evolution of galaxies in the nearby universe at high resolution and over 5 orders of magnitude in column density. It will be a Nearby Galaxies Legacy Survey that will be unsurpassed until the advent of the SKA, and can serve as a highly visible, lasting statement of MeerKAT's capabilities., Comment: To be published in "MeerKAT Science: On the Pathway to the SKA". Proceedings of Science. Workshop held 25-27 May, 2016 Stellenbosch, South Africa

The aim of this chapter is to guide you to conduct your systems research project. It will start suggesting some ways to establish a research project based on traditional project management principles and compare it with ways in which a systems researcher might set a research project. It will then explain the importance of constructing a methodology for your research project and point out why systems researchers often adopt multimethodologies to carry out research. The chapter will then focus on how systems interventions can be developed to contribute to your research methodology with examples of multimethodology and systemic action research interventions that have been successfully used by prominent systems researchers in different contexts. The chapter will then take you through some steps normally used in conducting a research project, with an emphasis on systems research, covering an overview of research methods, negotiating relationships to get access to research sites, data collection and analysis methods, and ways to demonstrate rigor. Since this chapter covers a wide area, bridging systems interventions to ways in which conventional research is carried out, it will focus more on how systems interventions can be set up and implemented and provide a variety of references to help the reader find adequate information to carry out research expected of doctoral studies or research reports. It will also make reference to other chapters in the book to guide the readers to take effective action to complete a research project successfully.

This guide is designed for systems researchers – emerging and seasoned – searching for holistic approaches of inquiry into complexity, which the Systems Sciences provide.

The aim of this chapter is to guide you to conduct your systems research project. It will start suggesting some ways to establish a research project based on traditional project management principles and compare it with ways in which a systems researcher might set a research project. It will then explain the importance of constructing a methodology for your research project and point out why systems researchers often adopt multimethodologies to carry out research. The chapter will then focus on how systems interventions can be developed to contribute to your research methodology with examples of multimethodology and systemic action research interventions that have been successfully used by prominent systems researchers in different contexts. The chapter will then take you through some steps normally used in conducting a research project, with an emphasis on systems research, covering an overview of research methods, negotiating relationships to get access to research sites, data collection and analysis methods, and ways to demonstrate rigor. Since this chapter covers a wide area, bridging systems interventions to ways in which conventional research is carried out, it will focus more on how systems interventions can be set up and implemented and provide a variety of references to help the reader find adequate information to carry out research expected of doctoral studies or research reports. It will also make reference to other chapters in the book to guide the readers to take effective action to complete a research project successfully.

This guide is designed for systems researchers – emerging and seasoned – searching for holistic approaches of inquiry into complexity, which the Systems Sciences provide.

Contains fulltext : 172400.pdf (Publisher’s version ) (Open Access), Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis, and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

We present results of a blind 21cm HI-line imaging survey of a galaxy overdensity located behind the Milky Way at $\ell,b$ $\approx$ 160 deg, 0.5 deg. The overdensity corresponds to a Zone-of-Avoidance crossing of the Perseus-Pisces Supercluster filament. Although it is known that this filament contains an X-ray galaxy cluster (3C129) hosting two strong radio galaxies, little is known about galaxies associated with this potentially rich cluster because of the high Galactic dust extinction. We mapped a sky area of $\sim$9.6 sq.deg using the Westerbork Synthesis Radio Telescope in a hexagonal mosaic of 35 pointings observed for 12 hours each, in the radial velocity range $cz = 2400 - 16600$ km/s. The survey has a sensitivity of 0.36 mJy/beam rms at a velocity resolution of 16.5 km/s. We detected 211 galaxies, 62% of which have a near-infrared counterpart in the UKIDSS Galactic Plane Survey. We present a catalogue of the HI properties and an HI atlas containing total intensity maps, position-velocity diagrams, global HI profiles and UKIDSS counterpart images. For the resolved galaxies we also present HI velocity fields and radial HI surface density profiles. A brief analysis of the structures outlined by these galaxies finds that 87 of them lie at the distance of the Perseus-Pisces Supercluster ($cz \sim 4000 - 8000$ km/s) and seem to form part of the 3C129 cluster. Further 72 detections trace an overdensity at a velocity of $cz \approx$ 10000 km/s and seem to coincide with a structure predicted from mass density reconstructions in the first 2MASS Redshift Survey., Comment: 28 pages, 18 figures, 6 Tables, accepted for publication in MNRAS

A blind HI survey of the extragalactic sky behind the southern Milky Way has been conducted with the multibeam receiver on the 64-m Parkes radio telescope. The survey covers the Galactic longitude range 212 < l < 36 and Galactic latitudes |b| < 5, and yields 883 galaxies to a recessional velocity of 12,000 km/s. The survey covers the sky within the HIPASS area to greater sensitivity, finding lower HI-mass galaxies at all distances, and probing more completely the large-scale structures at and beyond the distance of the Great Attractor. Fifty-one percent of the HI detections have an optical/NIR counterpart in the literature. A further 27% have new counterparts found in existing, or newly obtained, optical/NIR images. The counterpart rate drops in regions of high foreground stellar crowding and extinction, and for low-HI mass objects. Only 8% of all counterparts have a previous optical redshift measurement. A notable new galaxy is HIZOA J1353-58, a possible companion to the Circinus galaxy. Merging this catalog with the similarly-conducted northern extension (Donley et al. 2005), large-scale structures are delineated, including those within the Puppis and Great Attractor regions, and the Local Void. Several newly-identified structures are revealed here for the first time. Three new galaxy concentrations (NW1, NW2 and NW3) are key in confirming the diagonal crossing of the Great Attractor Wall between the Norma cluster and the CIZA J1324.7-5736 cluster. Further contributors to the general mass overdensity in that area are two new clusters (CW1 and CW2) in the nearer Centaurus Wall, one of which forms part of the striking 180 deg (100/h Mpc) long filament that dominates the southern sky at velocities of ~3000 km/s, and the suggestion of a further Wall at the Great Attractor distance at slightly higher longitudes., Comment: Published in Astronomical Journal 9 February 2016 (accepted 26 September 2015); 42 pages, 7 tables, 18 figures, main figures data tables only available in the on-line version of journal

Contains fulltext : 172400.pdf (Publisher’s version ) (Open Access), Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis, and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

We present results of a blind 21cm HI-line imaging survey of a galaxy overdensity located behind the Milky Way at $\ell,b$ $\approx$ 160 deg, 0.5 deg. The overdensity corresponds to a Zone-of-Avoidance crossing of the Perseus-Pisces Supercluster filament. Although it is known that this filament contains an X-ray galaxy cluster (3C129) hosting two strong radio galaxies, little is known about galaxies associated with this potentially rich cluster because of the high Galactic dust extinction. We mapped a sky area of $\sim$9.6 sq.deg using the Westerbork Synthesis Radio Telescope in a hexagonal mosaic of 35 pointings observed for 12 hours each, in the radial velocity range $cz = 2400 - 16600$ km/s. The survey has a sensitivity of 0.36 mJy/beam rms at a velocity resolution of 16.5 km/s. We detected 211 galaxies, 62% of which have a near-infrared counterpart in the UKIDSS Galactic Plane Survey. We present a catalogue of the HI properties and an HI atlas containing total intensity maps, position-velocity diagrams, global HI profiles and UKIDSS counterpart images. For the resolved galaxies we also present HI velocity fields and radial HI surface density profiles. A brief analysis of the structures outlined by these galaxies finds that 87 of them lie at the distance of the Perseus-Pisces Supercluster ($cz \sim 4000 - 8000$ km/s) and seem to form part of the 3C129 cluster. Further 72 detections trace an overdensity at a velocity of $cz \approx$ 10000 km/s and seem to coincide with a structure predicted from mass density reconstructions in the first 2MASS Redshift Survey., Comment: 28 pages, 18 figures, 6 Tables, accepted for publication in MNRAS

A blind HI survey of the extragalactic sky behind the southern Milky Way has been conducted with the multibeam receiver on the 64-m Parkes radio telescope. The survey covers the Galactic longitude range 212 < l < 36 and Galactic latitudes |b| < 5, and yields 883 galaxies to a recessional velocity of 12,000 km/s. The survey covers the sky within the HIPASS area to greater sensitivity, finding lower HI-mass galaxies at all distances, and probing more completely the large-scale structures at and beyond the distance of the Great Attractor. Fifty-one percent of the HI detections have an optical/NIR counterpart in the literature. A further 27% have new counterparts found in existing, or newly obtained, optical/NIR images. The counterpart rate drops in regions of high foreground stellar crowding and extinction, and for low-HI mass objects. Only 8% of all counterparts have a previous optical redshift measurement. A notable new galaxy is HIZOA J1353-58, a possible companion to the Circinus galaxy. Merging this catalog with the similarly-conducted northern extension (Donley et al. 2005), large-scale structures are delineated, including those within the Puppis and Great Attractor regions, and the Local Void. Several newly-identified structures are revealed here for the first time. Three new galaxy concentrations (NW1, NW2 and NW3) are key in confirming the diagonal crossing of the Great Attractor Wall between the Norma cluster and the CIZA J1324.7-5736 cluster. Further contributors to the general mass overdensity in that area are two new clusters (CW1 and CW2) in the nearer Centaurus Wall, one of which forms part of the striking 180 deg (100/h Mpc) long filament that dominates the southern sky at velocities of ~3000 km/s, and the suggestion of a further Wall at the Great Attractor distance at slightly higher longitudes., Comment: Published in Astronomical Journal 9 February 2016 (accepted 26 September 2015); 42 pages, 7 tables, 18 figures, main figures data tables only available in the on-line version of journal

We present a description of the Prototype All-Sky Imager (PASI), a backend correlator and imager of the first station of the Long Wavelength Array (LWA1). PASI cross-correlates a live stream of 260 dual-polarization dipole antennas of the LWA1, creates all-sky images, and uploads them to the LWA-TV website in near real-time. PASI has recorded over 13,000 hours of all-sky images at frequencies between 10 and 88 MHz creating opportunities for new research and discoveries. We also report rate density and pulse energy density limits on transients at 38, 52, and 74 MHz, for pulse widths of 5 s. We limit transients at those frequencies with pulse energy densities of $>2.7\times 10^{-23}$, $>1.1\times 10^{-23}$, and $>2.8\times 10^{-23}$ J m$^{-2}$ Hz$^{-1}$ to have rate densities $<1.2\times10^{-4}$, $<5.6\times10^{-4}$, and $<7.2\times10^{-4}$ yr$^{-1}$ deg$^{-2}$, Comment: 27 pages, 10 Figures, 1 Table

We present a description of the Prototype All-Sky Imager (PASI), a backend correlator and imager of the first station of the Long Wavelength Array (LWA1). PASI cross-correlates a live stream of 260 dual-polarization dipole antennas of the LWA1, creates all-sky images, and uploads them to the LWA-TV website in near real-time. PASI has recorded over 13,000 hours of all-sky images at frequencies between 10 and 88 MHz creating opportunities for new research and discoveries. We also report rate density and pulse energy density limits on transients at 38, 52, and 74 MHz, for pulse widths of 5 s. We limit transients at those frequencies with pulse energy densities of $>2.7\times 10^{-23}$, $>1.1\times 10^{-23}$, and $>2.8\times 10^{-23}$ J m$^{-2}$ Hz$^{-1}$ to have rate densities $<1.2\times10^{-4}$, $<5.6\times10^{-4}$, and $<7.2\times10^{-4}$ yr$^{-1}$ deg$^{-2}$, Comment: 27 pages, 10 Figures, 1 Table

We present the findings from the Prototype All-Sky Imager (PASI), a backend correlator of the first station of the Long Wavelength Array (LWA1), which has recorded over 11,000 hours of all-sky images at frequencies between 25 and 75 MHz. In a search of this data for radio transients, we have found 49 long (10s of seconds) duration transients. Ten of these transients correlate both spatially and temporally with large meteors (fireballs), and their signatures suggest that fireballs emit a previously undiscovered low frequency, non-thermal pulse. This emission provides a new probe into the physics of meteors and identifies a new form of naturally occurring radio transient foreground., Comment: 14 Pages, 5 Figures

As a backend to the first station of the Long Wavelength Array (LWA1) the Prototype All Sky Imager (PASI) has been imaging the sky $>$ -26$^{\circ}$ declination during 34 Gamma Ray Bursts (GRBs) between January 2012 and May 2013. Using this data we were able to put the most stringent limits to date on prompt low frequency emission from GRBs. While our limits depend on the zenith angle of the observed GRB, we estimate a 1$\sigma$ RMS sensitivity of 68, 65 and 70 Jy for 5 second integrations at 37.9, 52.0, and 74.0 MHz at zenith. These limits are relevant for pulses $\geq$ 5 s and are limited by dispersion smearing. For pulses of length 5 s we are limited to dispersion measures ($DM$s) $\leq$ 220, 570, and 1,600 pc cm$^{-3}$ for the frequencies above. For pulses lasting longer than 5s, the $DM$ limits increase linearly with the duration of the pulse. We also report two interesting transients, which are, as of yet, of unknown origin, and are not coincident with any known GRBs. For general transients, we give rate density limits of $\leq$ $7.5\times10^{-3}$, $2.9\times10^{-2}$, and $1.4\times10^{-2}$ yr$^{-1}$ deg$^{-2}$ with pulse energy densities $>1.3\times 10^{-22}$, $1.1\times 10^{-22}$, and $1.4\times 10^{-22}$ J m$^{-2}$ Hz$^{-1}$ and pulse widths of 5 s at the frequencies given above., Comment: 11 pages, 6 figure, 3 tables, accepted for publication in ApJ

We present the findings from the Prototype All-Sky Imager (PASI), a backend correlator of the first station of the Long Wavelength Array (LWA1), which has recorded over 11,000 hours of all-sky images at frequencies between 25 and 75 MHz. In a search of this data for radio transients, we have found 49 long (10s of seconds) duration transients. Ten of these transients correlate both spatially and temporally with large meteors (fireballs), and their signatures suggest that fireballs emit a previously undiscovered low frequency, non-thermal pulse. This emission provides a new probe into the physics of meteors and identifies a new form of naturally occurring radio transient foreground., Comment: 14 Pages, 5 Figures

As a backend to the first station of the Long Wavelength Array (LWA1) the Prototype All Sky Imager (PASI) has been imaging the sky $>$ -26$^{\circ}$ declination during 34 Gamma Ray Bursts (GRBs) between January 2012 and May 2013. Using this data we were able to put the most stringent limits to date on prompt low frequency emission from GRBs. While our limits depend on the zenith angle of the observed GRB, we estimate a 1$\sigma$ RMS sensitivity of 68, 65 and 70 Jy for 5 second integrations at 37.9, 52.0, and 74.0 MHz at zenith. These limits are relevant for pulses $\geq$ 5 s and are limited by dispersion smearing. For pulses of length 5 s we are limited to dispersion measures ($DM$s) $\leq$ 220, 570, and 1,600 pc cm$^{-3}$ for the frequencies above. For pulses lasting longer than 5s, the $DM$ limits increase linearly with the duration of the pulse. We also report two interesting transients, which are, as of yet, of unknown origin, and are not coincident with any known GRBs. For general transients, we give rate density limits of $\leq$ $7.5\times10^{-3}$, $2.9\times10^{-2}$, and $1.4\times10^{-2}$ yr$^{-1}$ deg$^{-2}$ with pulse energy densities $>1.3\times 10^{-22}$, $1.1\times 10^{-22}$, and $1.4\times 10^{-22}$ J m$^{-2}$ Hz$^{-1}$ and pulse widths of 5 s at the frequencies given above., Comment: 11 pages, 6 figure, 3 tables, accepted for publication in ApJ

We present flux density measurements and pulse profiles for the millisecond pulsar PSR J2145-0750 spanning 37 to 81 MHz using data obtained from the first station of the Long Wavelength Array. These measurements represent the lowest frequency detection of pulsed emission from a millisecond pulsar to date. We find that the pulse profile is similar to that observed at 102 MHz. We also find that the flux density spectrum between ~40 MHz to 5 GHz is suggestive of a break and may be better fit by a model that includes spectral curvature with a rollover around 730 MHz rather than a single power law., Comment: accepted to the Astrophysical Journal Letters; 14 pages, 4 figures

We present flux density measurements and pulse profiles for the millisecond pulsar PSR J2145-0750 spanning 37 to 81 MHz using data obtained from the first station of the Long Wavelength Array. These measurements represent the lowest frequency detection of pulsed emission from a millisecond pulsar to date. We find that the pulse profile is similar to that observed at 102 MHz. We also find that the flux density spectrum between ~40 MHz to 5 GHz is suggestive of a break and may be better fit by a model that includes spectral curvature with a rollover around 730 MHz rather than a single power law., Comment: accepted to the Astrophysical Journal Letters; 14 pages, 4 figures

We present flux density measurements and pulse profiles for the millisecond pulsar PSR J2145-0750 spanning 37 to 81 MHz using data obtained from the first station of the Long Wavelength Array. These measurements represent the lowest frequency detection of pulsed emission from a millisecond pulsar to date. We find that the pulse profile is similar to that observed at 102 MHz. We also find that the flux density spectrum between approximate to 40 MHz to 5 GHz is suggestive of a break and may be better fit by a model that includes spectral curvature with a rollover around 730 MHz rather than a single power law.