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Omadacycline is novel, aminomethyl tetracycline antibiotic being developed for oral and intravenous (IV) administration for the treatment of community-acquired bacterial infections. ...Omadacycline is characterized by an aminomethyl substituent at the C9 position of the core 6-member ring. Modifications at this position result in an improved spectrum of antimicrobial activity by overcoming resistance known to affect older generation tetracyclines via ribosomal protection proteins and efflux pump mechanisms. In vitro, omadacycline has activity against Gram-positive and Gram-negative aerobes, anaerobes, and atypical pathogens including Legionella and Chlamydia spp. Omadacycline offers once daily oral and IV dosing and a clinical tolerability and safety profile that compares favorably with contemporary antibiotics used across serious community-acquired infections where resistance has rendered many less effective. In studies in patients with complicated skin and skin structure infections, including those with MRSA infections, omadacycline exhibited an efficacy and tolerability profile that was comparable to linezolid. Ongoing and planned clinical studies are evaluating omadacycline as monotherapy for treating serious community-acquired bacterial infections including Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP). This review provides an overview of the discovery, microbiology, nonclinical data, and available clinical safety and efficacy data for omadacycline, with reference to other contemporary tetracycline-derived antibiotics.
Maintaining undifferentiated mouse embryonic stem cell (mESC) culture has been a major challenge as mESCs cultured in Leukemia Inhibitory Factor (LIF) conditions exhibit spontaneous differentiation, ...fluctuating expression of pluripotency genes, and genes of specialized cells. Here we show that, in sharp contrast to the mESCs seeded on the conventional rigid substrates, the mESCs cultured on the soft substrates that match the intrinsic stiffness of the mESCs and in the absence of exogenous LIF for 5 days, surprisingly still generated homogeneous undifferentiated colonies, maintained high levels of Oct3/4, Nanog, and Alkaline Phosphatase (AP) activities, and formed embryoid bodies and teratomas efficiently. A different line of mESCs, cultured on the soft substrates without exogenous LIF, maintained the capacity of generating homogeneous undifferentiated colonies with relatively high levels of Oct3/4 and AP activities, up to at least 15 passages, suggesting that this soft substrate approach applies to long term culture of different mESC lines. mESC colonies on these soft substrates without LIF generated low cell-matrix tractions and low stiffness. Both tractions and stiffness of the colonies increased with substrate stiffness, accompanied by downregulation of Oct3/4 expression. Our findings demonstrate that mESC self-renewal and pluripotency can be maintained homogeneously on soft substrates via the biophysical mechanism of facilitating generation of low cell-matrix tractions.
During an explosion, the interfaces of welded materials experience fast heating due to high strain rate severe plastic deformation. This leads to the formation of local zones, where melting and ...mixing of welded materials is observed. These zones are frequently referred to as vortexes, eddies or swirls, due to the specific rotational movement of materials during mixing. This study is primarily devoted to the discussion of the structures that appear in these zones. Simple approaches to estimate the heating and cooling rates at the interfaces between explosively welded materials were proposed. It was concluded that the heating rate at the interfaces was of the order of 109 K/s, while the cooling rate achieved 107 K/s. Several combinations of explosively welded alloys (steel/steel, Ti alloy/steel, Zr/Cu, Zr/Ni, Ta/Cu, Al/magnesium alloy and Cu/brass) were thoroughly analyzed using scanning electron microscopy, transmission electron microscopy and energy dispersive X-ray spectroscopy. In most of these combinations, metastable crystalline, quasicrystalline or glassy phases were observed. The formation of different types of metastable phases is discussed with respect to the compositions of the welded alloys. It was concluded that solidification conditions at the interfaces of explosively welded materials are similar to those during rapid solidification. Thus, the results of numerous experiments on rapid solidification of alloys could be applied to analyze the structures that appear in mixing zones.
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Bacterial wilt is a serious problem affecting many important food crops. Recent studies have indicated that treatment with biotic or abiotic stress factors may increase the resistance of plants to ...bacterial infection. This study investigated the effects of magnesium oxide nanoparticles (MgO NP) on disease resistance in tomato plants against Ralstonia solanacearum, as well as its antibacterial activity. The roots of tomato seedlings were inoculated with R. solanacearum and then immediately treated with MgO NP; the treated plants showed very little inhibition of bacterial wilt. In contrast, when roots were drenched with a MgO NP suspension prior to inoculation with the pathogen, the incidence of disease was significantly reduced. Rapid generation of reactive oxygen species such as O₂ ⁻˙ radicals was observed in tomato roots treated with MgO NP. Further O₂ ⁻˙ was rapidly generated when tomato plant extracts or polyphenols were added to the MgO NP suspension, suggesting that the generation of O₂ ⁻˙ in tomato roots might be due to a reaction between MgO NP and polyphenols present in the roots. Salicylic acid‐inducible PR1, jasmonic acid‐inducible LoxA, ethylene‐inducible Osm, and systemic resistance‐related GluA were up‐regulated in both the roots and hypocotyls of tomato plants after treatment of the plant roots with MgO NP. Histochemical analyses showed that β‐1,3‐glucanase and tyloses accumulated in the xylem and apoplast of pith tissues of the hypocotyls after MgO NP treatment. These results indicate that MgO NP induces systemic resistance in tomato plants against R. solanacearum.
Many replication proteins assemble on the pre-RC-formed replication origins and constitute the pre-initiation complex (pre-IC). This complex formation facilitates the conversion of Mcm2-7 in the ...pre-RC to an active DNA helicase, the Cdc45-Mcm-GINS (CMG) complex. Two protein kinases, cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK), work to complete the formation of the pre-IC. Each kinase is responsible for a distinct step of the process in yeast; Cdc45 associates with origins in a DDK-dependent manner, whereas the association of GINS with origins depends on CDK. These associations with origins also require specific initiation proteins: Sld3 for Cdc45; and Dpb11, Sld2, and Sld3 for GINS. Functional homologs of these proteins exist in metazoa, although pre-IC formation cannot be separated by requirement of DDK and CDK because of experimental limitations. Once the replicative helicase is activated, the origin DNA is unwound, and bidirectional replication forks are established.
Summary
This cohort study of 1,614 postmenopausal Japanese women followed for 6.7 years showed that overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture ...risk assessment may be improved if fracture sites are taken into account and BMI is categorized.
Introduction
The effect of body mass index (BMI) on fracture at a given level of bone mineral density (BMD) is controversial, since varying associations between BMI and fracture sites have been reported.
Methods
A total of 1,614 postmenopausal Japanese women were followed for 6.7 years in a hospital-based cohort study. Endpoints included incident vertebral, femoral neck, and long-bone fractures. Rate ratios were estimated by Poisson regression models adjusted for age, diabetes mellitus, BMD, prior fracture, back pain, and treatment by estrogen.
Results
Over a mean follow-up period of 6.7 years, a total of 254 clinical and 335 morphometric vertebral fractures, 48 femoral neck fractures, and 159 long-bone fractures were observed. Incidence rates of vertebral fracture in underweight and normal weight women were significantly lower than overweight or obese women by 0.45 (95 % confidence interval: 0.32 to 0.63) and 0.61 (0.50 to 0.74), respectively, if BMD and other risk factors were adjusted, and by 0.66 (0.48 to 0.90) and 0.70 (0.58 to 0.84) if only BMD was not adjusted. Incidence rates of femoral neck and long-bone fractures in the underweight group were higher than the overweight/obese group by 2.15 (0.73 to 6.34) and 1.51 (0.82 to 2.77) and were similar between normal weight and overweight/obesity.
Conclusions
Overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture risk assessment may be improved if fracture sites are taken into account and BMI is categorized.
Summary
In a 4-year follow-up study that enrolled 1099 subjects aged ≥60 years, sarcopenia prevalence was estimated at 8.2%. Moreover, the presence of osteoporosis was significantly associated with ...short-term sarcopenia occurrence, but the reciprocal relationship was not observed, suggesting that osteoporosis would increase the risk of osteoporotic fracture and sarcopenia occurrence.
Introduction
The present 4-year follow-up study was performed to clarify the prevalence, incidence, and relationships between sarcopenia (SP) and osteoporosis (OP) in older Japanese men and women.
Methods
We enrolled 1099 participants (aged, ≥60 years; 377 men) from the second survey of the Research on Osteoarthritis/Osteoporosis against Disability (ROAD) study (2008–2010) and followed them up for 4 years. Handgrip strength, gait speed, skeletal muscle mass, and bone mineral density were assessed. SP was defined according to the Asian Working Group for Sarcopenia. OP was defined based on the World Health Organization criteria.
Results
SP prevalence was 8.2% (men, 8.5%; women, 8.0%) in the second survey. In those with SP, 57.8% (21.9%; 77.6%) had OP at the lumbar spine L2–4 and/or femoral neck. SP cumulative incidence was 2.0%/year (2.2%/year; 1.9%/year). Multivariate regression analysis revealed that OP was significantly associated with SP occurrence within 4 years (odds ratio, 2.99; 95% confidence interval, 1.46–6.12;
p
< 0.01), but the reciprocal relationship was not significantly observed (2.11; 0.59–7.59;
p
= 0.25).
Conclusions
OP might raise the short-term risk of SP incidence. Therefore, OP would not only increase the risk for osteoporotic fracture but may also increase the risk for SP occurrence.
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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