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Possible aerosol-cloud-precipitation effects over Germany are investigated using the COSMO model in a convection-permitting configuration close to the operational COSMO-DE. Aerosol effects on clouds and precipitation are modeled by using an advanced two-moment microphysical parameterization taking into account aerosol assumptions for cloud condensation nuclei (CCN) as well as ice nuclei (IN). Simulations of three summer seasons have been performed with various aerosol assumptions, and are analysed regarding surface precipitation, cloud properties, and the indirect aerosol effect on near-surface temperature. We find that the CCN and IN assumptions have a strong effect on cloud properties, like condensate amounts of cloud water, snow and rain as well as on the glaciation of the clouds, but the effects on surface precipitation are – when averaged over space and time – small. This robustness can only be understood by the combined action of microphysical and dynamical processes. On one hand, this shows that clouds can be interpreted as a buffered system where significant changes to environmental parameters, like aerosols, have little effect on the resulting surface precipitation. On the other hand, this buffering is not active for the radiative effects of clouds, and the changes in cloud properties due to aerosol perturbations may have a significant effect on radiation and near-surface temperature.

To date no comprehensive evaluation has appraised the likelihood of bias or the strength of the evidence of peripheral biomarkers for bipolar disorder (BD). Here we performed an umbrella review of meta-analyses of peripheral non-genetic biomarkers for BD. The Pubmed/Medline, EMBASE and PsycInfo electronic databases were searched up to May 2015. Two independent authors conducted searches, examined references for eligibility, and extracted data. Meta-analyses in any language examining peripheral non-genetic biomarkers in participants with BD (across different mood states) compared to unaffected controls were included. Six references, which examined 13 biomarkers across 20 meta-analyses (5474 BD cases and 4823 healthy controls) met inclusion criteria. Evidence for excess of significance bias (i.e. bias favoring publication of 'positive' nominally significant results) was observed in 11 meta-analyses. Heterogeneity was high for (I 2 ⩾ 50%) 16 meta-analyses. Only two biomarkers met criteria for suggestive evidence namely the soluble IL-2 receptor and morning cortisol. The median power of included studies, using the effect size of the largest dataset as the plausible true effect size of each meta-analysis, was 15.3%. Our findings suggest that there is an excess of statistically significant results in the literature of peripheral biomarkers for BD. Selective publication of 'positive' results and selective reporting of outcomes are possible mechanisms.

Background Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. Methods Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. Results Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. Conclusions YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies.

Genomic imprinting, the allele-specific expression of a gene dependent on its parent-of-origin, has independently evolved in flowering plants and mammals. In mammals and flowering plants, imprinting occurs in the embryo as well as in embryo-nourishing tissues, the placenta and the endosperm, respectively, and it has been suggested that imprinted genes control the nutrient flow from the mother to the offspring (‘kinship theory’). Alternatively, imprinting might have evolved as a by-product of a defense mechanism destined to control transposon activity in gametes (‘defense hypothesis’). Recent studies provide substantial evidence for the ‘defense hypothesis’ by showing that imprinted genes in plants are located in the vicinity of transposon or repeat sequences, suggesting that the insertion of transposon or repeat sequences was a prerequisite for imprinting evolution. Transposons or repeat sequences are silenced by DNA methylation, causing silencing of neighboring genes in vegetative tissues. However, because of genome-wide DNA demethylation in the central cell, genes located in the vicinity of transposon or repeat sequences will be active in the central cell and the maternal alleles will remain unmethylated and active in the descendent endosperm, assuming an imprinted expression. Consequently, many imprinted genes are likely to have an endosperm-restricted function, or, alternatively, they have no functional role in the endosperm and are on the trajectory to convert to pseudogenes. Thus, the ‘defense hypothesis’ as well as ‘kinship theory’ together can explain the origin of genomic imprinting; whereas the first hypothesis explains how imprinting originates, the latter explains how imprinting is manifested and maintained.

IntroductionNeoadjuvant (chemo)radiotherapy (n(C)RT) followed by resection with total mesorectal excision (TME) constitutes the standard treatment for patients with locally advanced rectal cancer of the middle and lower third. However, n(C)RT has demonstrated no significant impact on overall survival but is associated with adverse effects, including impaired sphincter and sexual function. We hypothesise that omitting n(C)RT in selected patients with a clear circumferential resection margin (CRM) >1 mm as determined through preoperative MRI is not inferior regarding local recurrence rate within 3 years after surgery. That treatment approach may show fewer adverse effects and be more cost-effective.Methods and analysisSelective neoadjuvant therapy of rectal cancer patients (SELREC) is a randomised controlled, parallel-group, open, multicentre, non-inferiority trial. The experimental intervention involves performing TME surgery without n(C)RT. In contrast, the control intervention adheres to German S3-guidelines, incorporating neoadjuvant radiotherapy (nRT) with a dosage of 5×5 Gy or a total of 50.4 Gy. Additionally, if applicable, concomitant chemotherapy (CT) based on 5-fluorouracil is administered, followed by TME surgery within less than 12 weeks. Adjuvant treatment according to guidelines is allowed depending on the (y)pTNM stage.The inclusion criteria for this study encompass adult patients with primary adenocarcinoma of the rectum in whom the main tumour mass is located less than 12 cm away from the anal verge, as assessed via proctoscopy. Additionally, eligible participants are required to have a preoperative tumour stage determined by MRI of either T1 or T2 with lymph node involvement (N1) or T3 with no lymph node involvement (N0) or with lymph node involvement (N1) and no distant metastases (M0). The assessment of a clear CRM >1 mm, based on MRI, is another prerequisite for inclusion. A total of 1074 patients in approximately 35 centres are planned to be allocated to the trial.The primary endpoint of the trial is local recurrence within 3 years after surgery. The primary estimand is based on the full analysis set using a logistic mixed model (margin 3%). The first secondary endpoint is no/minor low anterior resection syndrome (LARS) score at 2 years after surgery, and further secondary endpoints include survival outcomes and quality of life. Safety analysis involves describing the frequencies of major intervention-specific complications, such as the acute toxicity of n(C)RT according to CTCAE and perioperative morbidity and mortality according to Clavien-Dindo criteria.SELREC is financially supported by the German Federal Ministry of Education and Research.Ethics and disseminationThis trial has been prospectively registered in the German Clinical Trials Register.Previously, the study had been approved by the responsible ethics committee of Heidelberg and the local ethics committees of the collaborating institutions before patient enrolment. Any protocol deviation that has an impact on relevant parameters such as study design, endpoints or patient safety will be reported to the responsible ethics committees.The results will be published in a peer-reviewed scientific journal and on institutional websites.Trial registration numberGerman Clinical Trials Register DRKS00030567.

In this work we present a keV-scale sterile-neutrino search with a low-tritium-activity data set of the KATRIN experiment, acquired in a commissioning run in 2018. KATRIN performs a spectroscopic measurement of the tritium β -decay spectrum with the main goal of directly determining the effective electron anti-neutrino mass. During this commissioning phase a lower tritium activity facilitated the measurement of a wider part of the tritium spectrum and thus the search for sterile neutrinos with a mass of up to 1.6 keV . We do not find a signal and set an exclusion limit on the sterile-to-active mixing amplitude of sin 2 θ < 5 × 10 - 4 ( 95 % C.L.) at a mass of 0.3 keV. This result improves current laboratory-based bounds in the sterile-neutrino mass range between 0.1 and 1.0 keV.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality resulting from a direct or indirect injury of the lung. It is characterized by a rapid alveolar injury, lung inflammation with neutrophil accumulation, elevated permeability of the microvascular-barrier leading to an aggregation of protein-rich fluid in the lungs, followed by impaired oxygenation in the arteries and eventual respiratory failure. Very recently, we have shown an involvement of the Gq-coupled P2Y2 purinergic receptor (P2RY2) in allergic airway inflammation (AAI). In the current study, we aimed to elucidate the contribution of the P2RY2 in lipopolysaccharide (LPS)-induced ARDS mouse model. We found that the expression of P2ry2 in neutrophils, macrophages and lung tissue from animals with LPS-induced ARDS was strongly upregulated at mRNA level. In addition, ATP-neutralization by apyrase in vivo markedly attenuated inflammation and blocking of P2RY2 by non-selective antagonist suramin partially decreased inflammation. This was indicated by a reduction in the number of neutrophils, concentration of proinflammatory cytokines in the BALF, microvascular plasma leakage and reduced features of inflammation in histological analysis of the lung. P2RY2 blocking has also attenuated polymorphonuclear neutrophil (PMN) migration into the interstitium of the lungs in ARDS mouse model. Consistently, treatment of P2ry2 deficient mice with LPS lead to an amelioration of the inflammatory response showed by reduced number of neutrophils and concentrations of proinflammatory cytokines. In attempts to identify the cell type specific role of P2RY2, a series of experiments with conditional P2ry2 knockout animals were performed. We observed that P2ry2 expression in neutrophils, but not in the airway epithelial cells or CD4 + cells, was associated with the inflammatory features caused by ARDS. Altogether, our findings imply for the first time that increased endogenous ATP concentration via activation of P2RY2 is related to the pathogenesis of LPS-induced lung inflammation and may represent a potential therapeutic target for the treatment of ARDS and predictably assess new treatments in ARDS.

Results and discussion EVP signature for prognostic prediction CRLM survival Our discovery cohort (Table 1) included patients with CRLM (n = 56) or benign liver disease (n = 7; BD) and we observed that the EVP concentration in the serum of the CRLM patients was significantly increased in comparison to patients with BD (before surgery: p = 0.01; after surgery: p < 0.001; Fig. 1A). SEE PDF] Mass spectrometry (MS) is emerging as a valuable tool to gain insight into the biology and clinical utility of EVPs [11,12,13]. Here, we first examined the EVP composition in liquid biopsies of patients with CRLM using LC–MS with a cEV median particle size of 98.2 and a mean particle concentration of 3.5E + 11 (Supplementary Fig. 1A – D). CXCL7 was investigated in more detail as the CXCL7/CXCR2 axis has been implied to be a predictive marker of poor survival in metastatic CRC as well as a diagnostic serum marker in CRC [18, 19]. [...]only CXCL7 was downregulated after tumour removal with > twofold and FDR < 0.05 (Fig. 2B), suggesting metastatic lesions as major source of EV-bound CXCL7.

The endosperm is a reproductive tissue supporting embryo development. In most flowering plants, the initial divisions of endosperm nuclei are not succeeded by cellularization; this process occurs only after a specific number of mitotic cycles have taken place. The timing of cellularization significantly influences seed viability and size. Previous research implicated auxin as a key factor in initiating nuclear divisions and determining the timing of cellularization. Here we uncover the involvement of a family of clustered auxin response factors (cARFs) as dosage-sensitive regulators of endosperm cellularization. cARFs , maternally expressed and paternally silenced, are shown to induce cellularization, thereby restricting seed growth. Our findings align with the predictions of the parental conflict theory, suggesting that cARFs represent major molecular targets in this conflict. We further demonstrate a recurring amplification of cARFs in the Brassicaceae, suggesting an evolutionary response to parental conflict by reinforcing maternal control over endosperm cellularization. Our study highlights that antagonistic parental control on endosperm cellularization converges on auxin biosynthesis and signalling. In most flowering plants, early divisions of endosperm nuclei are not succeeded by cellularization. This study uncovered a family of clustered auxin response factors as dosage-sensitive, maternally expressed regulators of endosperm cellularization.

Background and aims Liver cancer is the third leading cause of cancer related death due to treatment resistance and late onset of symptoms (Rumgay in J Hepatol 77: 1598–1606, 2022). The role of external beam radiotherapy (EBRT) in treatment of unresectable liver cancer needs to be defined. The use of particle therapy such as carbon ion radiation therapy (CIRT) with high linear energy transfer (LET) could increase efficacy of EBRT while limiting the toxic effects of radiation on non-cancerous liver tissue. Promising effects of CIRT have been described in several studies during the past decades, mostly in Japan. To date, no standardized treatment protocol has been established and European data on CIRT for liver cancer is lacking. This retrospective analysis aims to investigate efficacy and safety of hypofractionated CIRT compared to photon-based stereotactic body radiation (SBRT) in primary liver cancer. Method Thirty-six (n = 36) and twenty (n = 20) patients with primary malignant liver tumors were treated with hypofractionated CIRT (4 fractions) and photon-based SBRT, respectively, between 2011 and 2022 and were retrospectively evaluated for survival, local control, and toxicity. Results Two-year local control rate after CIRT was 92.3%. Compared to photon- based SBRT, CIRT scores with a significantly longer median distant progression free survival (3.1 versus 0.9 years). In a matched pair comparison of the two treatment regimens, the CIRT cohort demonstrated both longer 2-year overall survival (100% versus 59.6%) and longer 2-year distant PFS (75.7% versus 22.9%). No significant impairment of liver function was observed in either cohort. Conclusion In this retrospective analysis, patients who received CIRT presented excellent local tumor control and had better oncologic outcomes than patients who received photon-based SBRT. SBRT with carbon ions is a promising local ablative treatment option that needs further investigation in large prospective trials.