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Globular clusters are some of the oldest bound stellar structures observed in the Universe 1 . They are ubiquitous in large galaxies and are believed to trace intense star-formation events and the hierarchical build-up of structure 2 , 3 . Observations of globular clusters in the Milky Way, and a wide variety of other galaxies, have found evidence for a ‘ metallicity floor ’ , whereby no globular clusters are found with chemical (metal) abundances below approximately 0.3 to 0.4 per cent of that of the Sun 4 – 6 . The existence of this metallicity floor may reflect a minimum mass and a maximum redshift for surviving globular clusters to form—both critical components for understanding the build-up of mass in the Universe 7 . Here we report measurements from the Southern Stellar Streams Spectroscopic Survey of the spatially thin, dynamically cold Phoenix stellar stream in the halo of the Milky Way. The properties of the Phoenix stream are consistent with it being the tidally disrupted remains of a globular cluster. However, its metal abundance ([Fe/H] = −2.7) is substantially below the empirical metallicity floor. The Phoenix stream thus represents the debris of the most metal-poor globular clusters discovered so far, and its progenitor is distinct from the present-day globular cluster population in the local Universe. Its existence implies that globular clusters below the metallicity floor have probably existed, but were destroyed during Galactic evolution. The Phoenix stream in the Milky Way halo is shown to be a tidally disrupted remnant of an unusually metal-poor globular cluster, which was possibly destroyed during Galactic evolution.

[This corrects the article DOI: 10.1371/journal.pone.0187748.].

The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis.

Use of faults in seismic hazard models allows us to capture the recurrence of large-magnitude events and therefore improve the reliability of probabilistic seismic hazard assessment (PSHA). In the past decades, fault segmentation provided an important framework for quantifying fault-based PSHA. Recent complex coseismic ruptures (e.g., 2010 Mw 7.1 Canterbury, 2012 Mw 8.6 Sumatra, 2016 Mw 7.8 Kaikōura, 2016 Mw 6.5 central Italy) have shown the need to consider different possible combinations of rupture scenarios in PSHA. Here we present two new methodologies that model rates of ruptures along complex fault systems, one based on a floating rupture approach (FRESH) and another one based on assumed rupture scenarios (SUNFISH). They represent alternatives to a recently proposed approach (SHERIFS), and further step to overcome the segmented and un-segmented approaches commonly used in PSHA in Europe. Differences among SHERIFS, SUNFiSH and FRESH are related to the way slip rate, rupture geometries and magnitude–frequency distributions are modelled. To quantify the differences between these three methodologies, we compared PSHA results based on geometries and slip rates of a fault system located in northeastern Italy, assuming a given maximum magnitude and the same seismic moment rate target. Differences up to 20–30% in the peak ground acceleration at 2% and 10% in 50 years are observed. Finally, we show that the three methodologies are able to solve for the long-term rate of ruptures with resulting PSHA that reflect the fault system geometry and slip rates, without any assumption on segment boundaries. Using fault-based approaches in PSHA requires collecting as much local geological information as possible. Now that multi-fault rupture approaches are available, simplifying assumptions often made to model complex fault systems (uniform slip rate, segmentation hypothesis) are no longer necessary. On the other hand, local data collection should be strongly encouraged to better characterize the actual fault slip rate variability and the complex 3D geometries.

Background The strength and size of core muscles, including the abdominal muscles, are crucial to proper function in most activities. Therefore, it is important to reliably assess these characteristics. Our primary objective was to determine if the length, thickness and cross-sectional area of the transversus abdominis (TrA) can be visualized independently from the internal and external abdominal oblique muscles using extended field of view ultrasound imaging at rest and with contraction and to establish its intra- and inter-tester reliability. Methods Twenty-six individuals were recruited to participate in the study (20 F, 6 M), average age 24.0 years (SD 9.4), height 170.7 cm (SD 8.6) and weight 63.9 kg (SD 9.0). From this total number of participants, two groups of 16 randomly selected participants were assessed to determine intra- and inter-tester reliability respectively. Extended field of view ultrasound images were obtained at three vertebral levels during rest and contraction in the side lying position for both the right and left sides of the trunk. Results Excellent intra-tester and inter-tester reliability was seen (ICC range of 0.972 to 0.984). The overall average percent standard error of the measurement for all measurements and locations was approximately 4%. The overall average minimal difference for the thickness measurement for the resting and contraction conditions combined were as follows: intratester 0.056 (0.014) cm and intertester 0.054 (0.017) cm, for area intratester 0.287 (0.086) cm 2 and intertester 0.289 (0.101) cm 2 and for length intratester 0.519 (0.097) cm and intertester 0.507 (0.085) cm. Conclusions Extended field of view ultrasound imaging is an effective method of reliably capturing clear images of the TrA during rest and contraction. It provides an efficient mechanism for the analysis of muscle morphology by being able to measure the cross-sectional area, thickness, and length on one image. This methodology is recommended for studies investigating TrA function and training.

Bone healing after internal fixation of intertrochanteric hip fractures is difficult to monitor with radiography, particularly with sliding hip screws (SHS). In this proof-of-concept study, we develop an ovine hip fracture model and use it to evaluate a novel sliding hip screw system with a sensor that can non-invasively detect bending of the screw implant during healing. An existing SHS implant was modified and implanted in a Suffolk Ewe sheep. A straight, radiodense 1 mm tungsten rod was attached to the screw in the cannula to enable quantification of screw bending by radiographically observing relative position of the rod compared to the screw tip. After surgery, weekly loaded and unloaded radiographs were taken of the femur. Once fracture stabilization had been indicated for at least three weeks, the femur was extracted and potted and radiographs were taken under simulated axial loading from 5 to 400 N. By week 3, full in vivo weight bearing over the fractured femur was achieved. In response, implant loading was clearly observed with the novel sensor. This observed implant loading continued until week 8, wherein it ceased entirely. Upon extraction, the femur showed a fully developed and very stable callus surrounding the fracture site. Subsequent mechanical tests confirmed no measurable implant loading under axial loads of up to 400 N. This test indicates that the proposed ovine model produces sufficient force over an SHS implant in an induced fracture. This allowed our sensor to indicate fracture healing through radiography in load scenarios greater than 25 kg.

Reflectance confocal microscopy (RCM) is an imaging device that permits non-invasive visualization of cellular morphology and has been shown to improve diagnostic accuracy of dermoscopically equivocal cutaneous lesions. The application of double reader concordance evaluation of dermoscopy-RCM image sets in retrospective settings and its potential application to telemedicine evaluation has not been tested in a large study population. To improve diagnostic sensitivity of RCM image diagnosis using a double reader concordance evaluation approach; to reduce mismanagement of equivocal cutaneous lesions in retrospective consultation and telemedicine settings. 1000 combined dermoscopy-RCM image sets were evaluated in blind by 10 readers with advanced training and internship in dermoscopy and RCM evaluation. We compared sensitivity and specificity of single reader evaluation versus double reader concordance evaluation as well as the effect of diagnostic confidence on lesion management in a retrospective setting. Single reader evaluation resulted in an overall sensitivity of 95.2% and specificity of 76.3%, with misdiagnosis of 8 melanomas, 4 basal cell carcinomas and 2 squamous cell carcinomas. Combined double reader evaluation resulted in an overall sensitivity of 98.3% and specificity of 65.5%, with misdiagnosis of 1 in-situ melanoma and 2 basal cell carcinomas. Evaluation of dermoscopy-RCM image sets of cutaneous lesions by single reader evaluation in retrospective settings is limited by sensitivity levels that may result in potential mismanagement of malignant lesions. Double reader blind concordance evaluation may improve the sensitivity of diagnosis and management safety. The use of a second check can be implemented in telemedicine settings where expert consultation and second opinions may be required.

Summary We studied factors to determine the receipt of osteoporosis treatment in individuals with osteoporosis. Treatment was associated with age, gender, race, body mass index (BMI), family history, arthritis and thyroid problems, daily glucocorticoid use, number of prescriptions and healthcare visits, and insurance type. Introduction Osteoporosis is underrecognized and undertreated. Few studies have examined factors associated with osteoporosis treatment in a large, national sample of men and women. Methods We aggregated National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2010 and created a subsample which included individuals 50 years or older who were identified to have osteoporosis either by self-report data or by bone density measurements. The primary outcome was the receipt of osteoporosis treatment either from self-report or from prescription records. Covariates included sociodemographics, clinical characteristics, and access to healthcare variables. Logistic regression analyses were performed to determine factors that associate with osteoporosis treatment. Results From a sample of 31,0134 participants, 1,133 subjects (3.65 %) met the study criteria. Treatment was associated with age (odds ratio (OR) = 1.14), gender (OR = 13.25), race (OR = 2.23, White vs. Black; OR = 1.76, other vs. Black), BMI (OR = 1.67, normal vs. obese; OR = 2.68, overweight vs. obese), family history of osteoporosis (OR = 1.94), arthritis (OR = 1.43), daily glucocorticoid use (OR = 1.43), number of prescriptions (OR = 1.01), and number of healthcare visits in the past year (OR = 1.44, 4–9 vs. 0–3 visits). All odds ratios were statistically significant. Conclusion A large number of individuals diagnosed with osteoporosis above the age of 50 remain untreated. It is important for healthcare providers to better assess older adults with osteoporosis, including individuals who frequently receive medical care.

Objective: We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. Design: Forebrain Shp2 −/− mice were generated by crossing Shp2 flox/flox mice with CamKIIα-cre mice. At 22–24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. Results: Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2 flox/flox control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2 flox/flox mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin’s ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. Conclusion: These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.