Sex determination is essential for the sexual reproduction to generate the next generation by the formation of functional male or female gametes. In mammals, primary sex determination is commenced by ...the presence or absence of the Y chromosome, which controls the fate of the gonadal primordium. The somatic precursor of gonads, the genital ridge is formed at the mid-gestation stage and gives rise to one of two organs, a testis or an ovary. The fate of the genital ridge, which is governed by the differentiation of somatic cells into Sertoli cells in the testes or granulosa cells in the ovaries, further determines the sex of an individual and their germ cells. Mutation studies in human patients with disorders of sex development and mouse models have revealed factors that are involved in mammalian sex determination. In most of mammals, a single genetic trigger, the Y-linked gene Sry (sex determination region on Y chromosome), regulates testicular differentiation. Despite identification of Sry in 1990, precise mechanisms underlying the sex determination of bipotential genital ridges are still largely unknown. Here, we review the recent progress that has provided new insights into the mechanisms underlying genital ridge formation as well as the regulation of Sry expression and its functions in male sex determination of mice.
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EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Growing evidence suggests that physical microenvironments and mechanical stresses, in addition to soluble factors, help direct mesenchymal-stem-cell fate. However, biological responses to a local ...force in embryonic stem cells remain elusive. Here we show that a local cyclic stress through focal adhesions induced spreading in mouse embryonic stem cells but not in mouse embryonic stem-cell-differentiated cells, which were ten times stiffer. This response was dictated by the cell material property (cell softness), suggesting that a threshold cell deformation is the key setpoint for triggering spreading responses. Traction quantification and pharmacological or shRNA intervention revealed that myosin II contractility, F-actin, Src or cdc42 were essential in the spreading response. The applied stress led to oct3/4 gene downregulation in mES cells. Our findings demonstrate that cell softness dictates cellular sensitivity to force, suggesting that local small forces might have far more important roles in early development of soft embryos than previously appreciated.
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IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Functionally graded materials are regarded as a special kind of composites capable of eliminating material interfaces and the delamination problems. Stress discontinuity can be avoided owing to ...smooth composition of the functionally graded ingredients. In this study, a recently emerged effective non-local continuum theory for solving fracture problems in solids and structures, peridynamics, is employed to simulate dynamic wave propagation as well as crack propagation in functionally graded materials. Specifically, the ordinary state-based formulation is adopted. The ordinary state-based formulation is slightly modified for the modelling of functionally graded materials. The averaging technique is employed to determine peridynamic parameters associated with the material properties. Firstly, a benchmark problem is considered to validate the present implementation of ordinary state-based peridynamics for brittle fracture of homogeneous materials. Then, the wave propagation in the functionally graded materials under impact loading is simulated. Finally, dynamic crack propagation in the functionally graded materials is studied. The evaluated crack paths and the displacement waves are compared with reference works including numerical and experimental results. Good agreement between the reference and present results is achieved. It is shown that a simple modification of ordinary state-based formulation has led to simulate dynamic fracture of functionally graded materials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Omadacycline, an aminomethylcycline, is an antibiotic that is approved in the United States for once-daily intravenous (i.v.) and oral use for treatment of adults with acute bacterial skin and skin ...structure infections and community-acquired bacterial pneumonia. In this thorough QT study, the effects of a therapeutic (100 mg i.v.) dose and a supratherapeutic (300 mg i.v.) dose of omadacycline on the electrocardiogram were studied, with placebo and moxifloxacin as negative and positive controls. Omadacycline at these doses had no effect on the QTc interval. The largest mean placebo-corrected change-from-baseline QTcS (ΔQTcS) were 1.7 ms (90% confidence interval CI, 0.06 to 3.30) and 2.6 ms (90% CI, 0.55 to 4.67), observed at 20 min and 2 h after the start of the infusion of 100 mg and 300 mg, respectively. Assay sensitivity was demonstrated with moxifloxacin, which caused clear prolongation of QTcS, with the largest mean placebo-corrected ΔQTcS of 9.8 ms at 1.5 and 2 h. With a linear exposure-response model, the estimated slope of the concentration-change-from-baseline QTcF (ΔQTcF) relationship was very shallow: 0.0007 ms per ng/ml (90% CI, 0.0000 to 0.0014). The possibility of an effect on placebo-corrected ΔQTcS exceeding 10 ms can be excluded at omadacycline concentrations in plasma of up to ∼8 μg/ml. Omadacycline had no effect on cardiac conduction (PR and QRS intervals) but caused an increase in heart rate of 16.8 beats per min at 35 min after the 100-mg dose and 21.6 beats per min at 50 min after the 300-mg dose.
The Hayabusa2 spacecraft arrived at the near-Earth carbonaceous asteroid 162173 Ryugu in 2018. We present Hayabusa2 observations of Ryugu's shape, mass, and geomorphology. Ryugu has an oblate ..."spinning top" shape, with a prominent circular equatorial ridge. Its bulk density, 1.19 ± 0.02 grams per cubic centimeter, indicates a high-porosity (>50%) interior. Large surface boulders suggest a rubble-pile structure. Surface slope analysis shows Ryugu's shape may have been produced from having once spun at twice the current rate. Coupled with the observed global material homogeneity, this suggests that Ryugu was reshaped by centrifugally induced deformation during a period of rapid rotation. From these remote-sensing investigations, we identified a suitable sample collection site on the equatorial ridge.
Summary
In this randomized, controlled trial, treatment with once-weekly subcutaneous injection of teriparatide for 72 weeks was found to be associated with a significant reduction in the incidence ...of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture.
Introduction
To determine whether the anti-fracture efficacy of teriparatide is superior to that of alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed.
Methods
Japanese women aged at least 75 years were eligible for the study if they had primary osteoporosis and were at high risk of fracture. Patients were randomly assigned in a 1:1 ratio to receive sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 μg for 72 weeks followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint was the incidence of morphometric vertebral fractures at 72 weeks (at the end of teriparatide treatment).
Results
Between October 2014 and December 2017, 1011 patients (505 in the teriparatide group and 506 in the alendronate group) were enrolled. Of these, 778 patients (351 and 427, respectively) were included in the primary analysis. The incidence of morphometric vertebral fractures was significantly lower in the teriparatide group (56 per 419.9 person-years, annual incidence rate 0.1334) than in the alendronate group (96 per 553.6 person-years, annual incidence rate 0.1734), with a rate ratio of 0.78 (95% confidence interval 0.61 to 0.99,
P
= 0.04). In both groups, adverse events were most frequently reported in the following system organ classes: infections and infestations, gastrointestinal disorders, and musculoskeletal and connective tissue disorders.
Conclusion
Once-weekly subcutaneous injection of teriparatide significantly reduced the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture.
Trial registration
jRCTs031180235 and UMIN000015573, March 12, 2019
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and ...molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
When the indication for surgery of highly advanced gastric cancer is considered, careful selection of the patients is important. In addition to tumor-node-metastasis factors and peritoneal ...lavage cytology (CY), which are important predictors of prognosis, detection of circulating tumor cells (CTCs) could be another potential marker.
Methods
This study prospectively evaluated CTCs using a semi-automated immunomagnetic separation system (CellSearch) for 136 patients with advanced gastric cancer to determine the frequency of CTC positivity. For 123 patients who also had their CY evaluated, the significance of both CTC and CY, was investigated as a potential biomarker to predict progression-free survival (PFS) or to monitor the therapeutic effect.
Results
In 25 patients (18.4 %), CTCs were positive. Positive CTC counts were more common for tumors with diffuse histologic type and distant metastasis. The PFS of CTC-positive patients was significantly shorter than that of CTC-negative patients (hazard ratio 2.03;
P
= 0.016). A multivariate analysis of 123 patients showed that CTC and CY as well as performance status and macroscopic distant metastasis were independent factors for PFS. When both CTC and CY were converted to negative values by therapeutic interventions, long-term PFS was achieved.
Conclusions
Detection of CTCs was an independent predictor of a shorter PFS in advanced gastric cancer. For selecting patients who require intensive treatment, CTCs could be a valuable biomarker. The combined status of CTC and CY would be useful in selecting patients for radical surgery. Further investigation with a larger number of patients is necessary to establish the importance of CTCs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary Objective To clarify the association between the occurrence and progression of knee osteoarthritis (KOA) with components of metabolic syndrome (MS), including overweight (OW), hypertension ...(HT), dyslipidaemia (DL), and impaired glucose tolerance (IGT), in a general population. Design From the large-scale population-based cohort study entitled Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) initiated in 2005, 1,690 participants (596 men, 1,094 women) residing in mountainous and coastal areas were enrolled. Of these, 1,384 individuals (81.9%; 466 men, 918 women) completed the second survey, including knee radiography, 3 years later. KOA was defined as Kellgren–Lawrence (KL) grade ≥ 2 using paired X-ray films. Based on changes in KL grades between the baseline and second surveys, cumulative incidence and progression of KOA were determined. OW, HT, DL, and IGT at baseline were assessed using standard criteria. Results The cumulative incidence of KOA among 1,384 completers over 3 years was 3.3%/year, and progression in KL grades for either knee, 8.0%/year. Logistic regression analyses after adjusting for potential risk factors revealed that the odds ratio (OR) for the occurrence of KOA significantly increased according to the number of MS components present (OR vs no component: one component, 2.33; two components, 2.82; ≥three components, 9.83). Similarly, progression of KOA significantly increased according to the number of MS components present (OR vs no component: one component, 1.38; two components, 2.29; ≥three components: 2.80). Conclusion Accumulation of MS components is significantly related to both occurrence and progression of KOA. MS prevention may be useful in reducing future KOA risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The near-Earth asteroid 162173 Ryugu, the target of the Hayabusa2 sample-return mission, is thought to be a primitive carbonaceous object. We report reflectance spectra of Ryugu's surface acquired ...with the Near-Infrared Spectrometer (NIRS3) on Hayabusa2, to provide direct measurements of the surface composition and geological context for the returned samples. A weak, narrow absorption feature centered at 2.72 micrometers was detected across the entire observed surface, indicating that hydroxyl (OH)-bearing minerals are ubiquitous there. The intensity of the OH feature and low albedo are similar to thermally and/or shock-metamorphosed carbonaceous chondrite meteorites. There are few variations in the OH-band position, which is consistent with Ryugu being a compositionally homogeneous rubble-pile object generated from impact fragments of an undifferentiated aqueously altered parent body.
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