Ebbesenlancaster9491

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigate 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood adiposity, only IGF-1 (OR 1.08 [1.03 1.15]), testosterone (total/free/bioavailable ~ OR 1.12 [1.05 1.20]), age at menopause (OR 1.05 [1.03 1.07]), and age at menarche (OR 0.92 [0.86 0.99], direct effect) influence breast cancer risk. However, multivariable Mendelian randomization analysis shows that the protective effect of childhood body size remains unaffected when accounting for these traits (ORs 0.59-0.67). This suggests that none of the investigated potential mediators strongly contribute to the protective effect of childhood adiposity on breast cancer risk individually. It is plausible, however, that several related traits could collectively mediate the effect when analysed together, and this work provides a compelling foundation for investigating other mediating pathways in future studies.

Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms.

The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdown/overexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin.

Plumbagin showed higher blood-brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death.

Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.

Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.Biological invasions are a grave threat to ecosystems. The black garden ant (Lasius niger) is a pest species in Europe. Current literature states that L. niger occupies a disjunct native distribution in the Holarctic, however, based on recent work, we re-evaluate this distribution. The native range of L. niger is reconsidered based on phylogenetic relationships (nine mitochondrial and nuclear markers, 5670 bp), DNA-barcoding (98 Holarctic specimens), morphometry (88 Holarctic specimens, 19 different measurements) and subjective assessment of phenotype. The potential spread of this species is estimated using ecological niche modeling. Lasius niger is more closely related to other Palearctic species than to the Nearctic ants known under this name. The latter are described as a distinct species, L. ponderosae sp. nov. However, DNA-barcoding discovered established populations of L. niger in metropolitan areas in Canada (Vancouver and Halifax). We describe a morphometrical method to delineate L. ponderosae sp. nov. SGCCBP30 and L. niger. MtDNA diversity and divergence is high within L. ponderosae sp. nov., but low within L. niger. More than 1,000,000 km2 are suitable as a habitat for L. niger in North America. This case emphasizes the critical role of integrative taxonomy to detect cryptic species and identify potential biological invasions in their nascent stages.The comparative effectiveness of different inhaler therapies in mild-to-moderate asthma remains unclear. To assess this, we performed a systematic review and network meta-analysis of randomized controlled trials on the use of inhalers for mild-to-moderate asthma by searching PubMed, Cochrane, and Embase. A total of 29 trials including 43,515 patients and 12 types of inhaler therapies were included. For the prevention of severe and moderate-to-severe exacerbations, inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) as maintenance and reliever (SMART) showed the highest rank for effectiveness. As-needed ICS/LABA or short-acting β2-agonist (SABA) was similar to low-dose ICS and superior to as-needed SABA or LABA for the prevention of severe and moderate-severe exacerbations. As for lung function (FEV1), low-dose ICS/LABA had the highest rank; as-needed ICS/LABA was inferior to regular low-dose ICS but superior to placebo. Higher-dose ICS had a superior effect on the Asthma Control Questionnaire (ACQ) scores, and as-needed ICS/LABA and as-needed SABA or LABA had lower ranks in p-rankogram than did the regular use of low-dose ICS. As-needed ICS with LABA or SABA was more effective than a similar dose of regular ICS for preventing exacerbation in mild-to-moderate asthma. As-needed ICS showed some weakness in improving lung function and controlling asthma symptoms.Since its identification, Saccharomyces eubayanus has been recognized as the missing parent of the lager hybrid, S. pastorianus. This wild yeast has never been isolated from fermentation environments, thus representing an interesting candidate for evolutionary, ecological and genetic studies. However, it is imperative to develop additional molecular genetics tools to ease manipulation and thus facilitate future studies. With this in mind, we generated a collection of stable haploid strains representative of three main lineages described in S. eubayanus (PB-1, PB-2 and PB-3), by deleting the HO gene using CRISPR-Cas9 and tetrad micromanipulation. Phenotypic characterization under different conditions demonstrated that the haploid derivates were extremely similar to their parental strains. Genomic analysis in three strains highlighted a likely low frequency of off-targets, and sequencing of a single tetrad evidenced no structural variants in any of the haploid spores. Finally, we demonstrate the utilization of the haploid set by challenging the strains under mass-mating conditions. In this way, we found that S. eubayanus under liquid conditions has a preference to remain in a haploid state, unlike S. cerevisiae that mates rapidly. This haploid resource is a novel set of strains for future yeast molecular genetics studies.Optical metasurfaces are researched more and more intensively for the possible realization of lightweight and compact optical devices with novel functionalities. In this paper, a new beam-steering system based on double metasurface lenses (metalenses) is proposed and developed. The proposed system is lightweight, small volume, low cost, and easy to integrate. The exact close-form forward and numerical inverse solutions are derived respectively using the generalized Snell's law of refraction. Given the orientations of the double metalenses, the pointing position can be accurately determined. If the desired pointing position is given, the required metalenses' orientations can be obtained by applied global optimization algorithms to solve nonlinear equations related to the inverse problem. The relationships of the scan region and blind zone with the system parameters are derived. The method to eliminate the blind zone is given. Comparison with double Risley-prism systems is also conducted. This work provides a new approach to control light beams.This study investigated the impact of experience on the visual behavior and driving performance of high-speed train drivers, and explored the correlation between visual behavior and driving performance. Through a simulated driving task, eye movement data and operating data of novice drivers, trainee drivers, and experienced drivers in the traction stage, normal operation process stage, and braking stage were collected. Variance and linear regression were used to analyze the difference and correlation between indicators. The results show that experience could change the driver's information collection method from long fixation to multi-frequency. Experience also increased the consistency of group operations and reduced the likelihood of hazard occurrences. Therefore, driving performance can be improved by reducing the average fixation duration of information through interface optimization.Myelodysplastic syndromes (MDS) are a group of clonal hematological disease with high risk of progression to AML. Accurate risk stratification is of importance for the proper management of MDS. Genetic lesions (Cytogenetic and Molecular mutations) are known to help in prognosticating the MDS patients. We have studied 152 MDS patients using cytogenetics and next generation sequencing (NGS). These patients were evaluated and as per cytogenetic prognostic group, majority (92.1%) of the patients classified as good (81.6%) and intermediate (10.5%) group. The NGS identified 38 different gene mutations in our cohort. Among 111 MDS patients with mutations, the most frequent mutated genes were SF3B1 (25.2%), SRSF2 (19%) U2AF1 (14.4%) ASXL1 (9.9%) RUNX1 (9.9%) TET2 (9%), TP53 (9%), ATM (6.3%), NRAS (5.4%) and JAK2/3 (5.4%). The survival analysis revealed that the mutations in TP53, JAK2/3, KRAS, NRAS and ASXL1 were significantly (P  less then  0.05) associated with poor survival of the patients. The univariate cox and multivariate cox analysis of our study suggested that the age, marrow morphology, cytogenetic and gene mutations with IPSS-R should be considered for prognosticating the MDS patients. We have proposed M-IPSS-R which changed the risk stratification i.e. 66.3% patients had decreased risk whereas 33.75% showed increased risk compared to IPSS-R. The survival analysis also showed that the M-IPSS-R were more significant in separating the patients as per their risk than the IPSS-R alone. The change in risk stratification could help in proper strategy for the treatment planning.Accurate pretreatment grading of pancreatic neuroendocrine tumors (PanNETs) is important to guide patient management. We aimed to evaluate endoscopic ultrasound-guided fine needle biopsy sampling (EUS-FNB) for the preoperative diagnosis and grading of PanNETs. In a tertiary-center setting, patients with suspected PanNETs were prospectively subjected to 22-gauge, reverse-bevel EUS-FNB. The EUS-FNB samples (Ki-67EUS) and corresponding surgical specimens (Ki-67SURG) were analyzed with Ki-67 indexing and thereafter tumor grading, (GRADEEUS) and (GRADESURG) respectively. In total 52 PanNET-patients [median age 66 years; females 25/52; surgical resection 22/52 (42%)] were included. EUS-FNB was diagnostic in 44/52 (85%). In 42 available FNB-slides, the median neoplastic cell count was 1034 (IQR 504-3667) with 32/42 (76%), 22/42 (52%), and 14/42 (33%) cases exceeding 500, 1000, and 2000 neoplastic cells respectively. Ki-67SURG was significantly higher compared to Ki-67EUS with a moderate correlation comparing Ki-67EUS and Ki-67SURG (Pearson r = 0.