Abstract
Microbial volatiles are important factors in symbiotic interactions with plants.
Mortierella hyalina
is a beneficial root-colonizing fungus with a garlic-like smell, and promotes growth of
...Arabidopsis
seedlings. GC–MS analysis of the
M. hyalina
headspace and NMR analysis of the extracted essential oil identified the sulfur-containing volatile tris(methylthio)methane (TMTM) as the major compound. Incorporation of the sulfur from the fungal volatile into plant metabolism was shown by
34
S labeling experiments. Under sulfur deficiency, TMTM down-regulated sulfur deficiency-responsive genes, prevented glucosinolate (GSL) and glutathione (GSH) diminishment, and sustained plant growth. However, excess TMTM led to accumulation of GSH and GSL and reduced plant growth. Since TMTM is not directly incorporated into cysteine, we propose that the volatile from
M. hyalina
influences the plant sulfur metabolism by interfering with the GSH metabolism, and alleviates sulfur imbalances under sulfur stress.
This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery ...compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.
Background and Purpose
Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3, and/or non‐Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with ...painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half‐life. However, topical modulation of PV autoantibody‐induced blistering is an attractive target because it could promptly relieve symptoms.
Experimental Approach
To address this issue, we performed an unbiased screening in a complex biological system using 141 low MW inhibitors from a chemical library. Specifically, we evaluated PV IgG‐induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model.
key Results
Overall, this approach led to the identification of four molecules involved in PV IgG‐induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2.
Conclusion and Implications
This unbiased screening revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life‐threatening skin disease.
BACKGROUND
A bolus dose of GnRH agonist can substitute for hCG as a trigger for the resumption of meiosis in ovarian stimulation with GnRH antagonists, which has been suggested to reduce the risk of ...ovarian hyperstimulation syndrome (OHSS). As the efficacy of this measure in fresh embryo transfer (ET) cycles is unclear, we evaluated a new clinical concept of GnRH-agonist triggering.
METHODS
In this prospective, observational proof-of-concept study, 20 patients considered at increased risk of developing OHSS (≥20 follicles ≥10 mm or estradiol ≥4000 pg/ml, or a history of cycle cancellation due to OHSS risk or the development of severe OHSS in a previous cycle) after ovarian stimulation and concomitant GnRH-antagonist administration had final oocyte maturation triggered with 0.2 mg triptorelin s.c. All two pronucleate (2 PN) oocytes were cryopreserved by vitrification, and frozen–thawed ETs (FT-ETs) were performed in an artificial cycle. Main outcome measures were the cumulative ongoing pregnancy rate per patient and the ongoing pregnancy rate per first ET. Secondary outcomes included the incidence of moderate-to-severe OHSS.
RESULTS
Of the 20 patients triggered with GnRH agonist, 19 patients underwent 24 FT-ETs in the observational period. The cumulative ongoing pregnancy rate was 36.8% (95% confidence interval: 19.1–59.0%). The ongoing pregnancy rate per first FT-ET was 31.6% (15.4–54.0%). No cases of moderate or severe OHSS were observed.
CONCLUSIONS
The present study is the proof of the concept that GnRH-agonist triggering of final oocyte maturation in combination with elective cryopreservation of 2 PN oocytes offers OHSS risk patients a good chance of pregnancy achievement, while reducing the risk of moderate and severe OHSS.
OBJECTIVES: Older adults often suffer from vitamin D deficiency and from the frailty syndrome charac-terized by different physical limitations, complicating independent everyday life. Previous ...studies have suggested a relationship between vitamin D status and the frailty syndrome, but results have been partly inconsistent, particularly regarding the shape of the association. Therefore, our aim was to further assess the association of 25-hydroxyvitamin D (25(OH)D) serum levels and frailty in older participants. DESIGN: Cross-sectional population-based study. PARTICIPANTS: The study population included 478 men and 462 women of the KORA (COoperative health research in the Region of Augsburg)-Age study born before 1944 examined in 2009. MEASUREMENTS: Classification of participants into different frailty states was performed according to the following criteria: weight loss, exhaustion, physical inactivity, slowness, and weakness. Participants who met 1−2 or ≥3 of the 5 criteria were classified as prefrail or frail, respectively. Total 25(OH)D was measured in non-fasting serum samples with an enhanced chemiluminescence immunoassay. Sequential logistic regression models adjusted for age, sex, season, lifestyle factors, diseases and biomarkers including parathyroid hormone (PTH) were calculated. RESULTS: High levels of 25(OH)D were inversely associated with being prefrail (N=351) or frail (N=38) in the model adjusted for age, sex, season and lifestyle factors. Compared to levels <15 ng/ml, odds ratios (ORs) (95% confidence intervals (CIs) were 0.52 (0.34–0.78) for levels of 15−<20 ng/ml, 0.55 (0.37–0.81) for levels of 20−<30 ng/ml and 0.32 (0.21–0.51) for levels ≥30 ng/ml. Additional adjustment for potential mediators including PTH only slightly attenuated these associations. For single frailty-components, significantly decreased ORs were found for exhaustion, physical inactivity and slowness comparing 25(OH)D levels ≥30 ng/ml with levels <15 ng/ml. CONCLUSION: Subjects with 25(OH)D serum levels ≥15 ng/ml were less frequently prefrail or frail.
Long-term follow-up studies on the health and the development of children conceived by assisted reproduction (ART) are mandatory to assess the safety of ART. Meanwhile, different aspects of health of ...these children have been studied. To put these results together, we performed a systematic review of these publications. A Pubmed search and a hand-search of the abstract books from the annual meeting of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine were performed for controlled studies on the developmental outcome of children after ART, which include a matching for plurality of gestation. Regarding general health, growth, mental and psychomotor development IVF children do not differ from spontaneously conceived (SC) children. An increased need for surgical interventions may be due to an increase in the malformation rate. However, a lower birth weight and lower gestational age compared to matched controls may contribute to some health problems observed. The increased risk of neurological problems found in some large registry-based studies can partly be explained by the higher frequency of twins born, by low birth weight, and by low gestational age also found in singletons. But an effect of IVF, the parents’ infertility or other factors not adjusted for in the studies cannot be excluded. In addition to this reporting bias caused by concerned parents cannot be excluded, either. To conclude, children born after assisted reproductive techniques are generally healthy and are developmentally similar to children born after SC. However, low birth weight and prematurity contributes to health care problems. An increase of neurological problems by IVF cannot be excluded. Further prospective studies on the neurological outcome are needed.
Strontium, carbon, and oxygen isotope data and radiocarbon ages document at least 30,000 years of hydrothermal activity driven by serpentinization reactions at Lost City. Serpentinization beneath ...this off-axis field is estimated to occur at a minimum rate of $1.2 \times 10^{-4}$ cubic kilometers per year. The access of seawater to relatively cool, fresh peridotite, coupled with faulting, volumetric expansion, and mass wasting processes, are crucial to sustain such systems. The amount of heat produced by serpentinization of peridotite massifs, typical of slow and ultraslow spreading environments, has the potential to drive Lost City-type systems for hundreds of thousands, possibly millions, of years.
To investigate general and electronic health literacy (HL) levels in prosthetic eye wearing patients, to define factors associated with reduced HL, and to identify a potential healthcare gap.
In this ...prospective cross-sectional study 148 prosthetic eye wearers were screened using the 16-item European Health Literacy Survey Questionnaire (HLS-EU-Q16) and the 8-item electronic Health Literacy Scale (eHEALS). HLS-EU-16 and eHEALS scores were correlated to health levels, vision functioning, and sociodemographic factors.
A total of 85 patients (57%) had adequate, 38 (26%) problematic, and 9 (6%) inadequate general HL, while 16 (11%) had no valid HLS-EU-Q16 score. General HL was positively correlated with physical health (p = 0.009) and negatively with a migration background (p = 0.023). There was a positive correlation between electronic HL and educational level (p < 0.001), social status (p = 0.048), and mental health (p = 0.013). Higher age was associated with lower electronic HL (p < 0.001).
More than 30% of the prosthetic eye wearers had problematic or even inadequate general HL, suggesting a significant health care gap. To identify patients with reduced HL, a standardized screening tool should be implemented as part of routine clinical care. Within integrated care, patients with insufficient HL should be offered barrier-free advisory services and information brochures in various languages.
Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. ...Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.
Synopsis
Chemokines and galectins are simultaneously upregulated during inflammation and mediate leukocyte recruitment. A systematic screen now demonstrates their physical interaction as heterodimers, identifying several novel interacting pairs.
Chemokines and galectins can engage in cross talk by pairing, as exemplified by galectin‐3 and CXCL12.
The association of CXCL12 with galectin‐3 appears to have potential for modulating chemokine activity.
Galectin‐3 inhibits CXCL12‐induced chemotaxis of leukocytes and their recruitment to inflammation sites.
Galectin‐3 attenuates CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex.
Chemokines and galectins are simultaneously upregulated during inflammation and mediate leukocyte recruitment. A systematic screen now demonstrates their physical interaction as heterodimers, identifying several novel interacting pairs.
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