Calibrating a high-resolution wavefront corrector with a static focal-plane camera

We present a method to calibrate a high-resolution wavefront (WF)-correcting device with a single, static camera, located in the focal-plane; no moving of any component is needed. The method is based on a localized diversity and differential optical transfer functions to compute both the phase and amplitude in the pupil plane located upstream of the last imaging optics. An experiment with a spatial light modulator shows that the calibration is sufficient to robustly operate a focal-plane WF sensing algorithm controlling a WF corrector with 40,000 degrees of freedom. We estimate that the locations of identical WF corrector elements are determined with a spatial resolution of 0.3% compared to the pupil diameter

Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice

DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting. Dyrk1A(−/−) null mutants presented a general growth delay and died during midgestation. Mice heterozygous for the mutation (Dyrk1A(+/−)) showed decreased neonatal viability and a significant body size reduction from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay of Dyrk1A(+/−) mice and specific alterations in adults. Brains of Dyrk1A(+/−) mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. These data provide evidence about the nonredundant, vital role of Dyrk1A and suggest a conserved mode of action that determines normal growth and brain size in both mice and flies

Radiofrequency-assisted transection of the pancreas vs stapler in distal pancreatectomy: a propensity score matched cohort analysis

[EN] To demonstrate the efficacy of radiofrequency for pancreatic stump closure in reducing the incidence of postoperative pancreatic fistula (POPF) in distal pancreatectomy (DP) compared with mechanical transection methods. Despite all the different techniques of pancreatic stump closure proposed for DP, best practice for avoiding POPF remains an unresolved issue, with an incidence of up to 30% regardless of center volume or surgical expertise. DP was performed in a cohort of patients by applying radiofrequency to stump closure (RF Group) and compared with mechanical closure (Control Group). A propensity score (PS) matched cohort study was carried out to minimize bias from nonrandomized treatment assignment. Cohorts were matched by PS accounting for factors significantly associated with either undergoing RF transection or mechanical closure through logistic regression analysis. The primary end-point was the incidence of clinically relevant POPF (CR-POPF). Of 89 patients included in the whole cohort, 13 case patients from the RF-Group were 1:1 matched to 13 control patients. In both the first independent analysis of unmatched data and subsequent adjustment to the overall propensity score-matched cohort, a higher rate of CR-POPF in the Control Group compared with the RF-Group was detected (25.4% vs 5.3%, p = 0.049 and 53.8% vs 0%; p = 0.016 respectively). The RF Group showed better outcomes in terms of readmission rate (46.2% vs 0%, p = 0.031). No significant differences were observed in terms of mortality, major complications (30.8% vs 0%, p = 0.063) or length of hospital stay (5.7 vs 5.2 days, p = 0.89). Findings suggest that the RF-assisted technique is more efficacious in reducing CR-POPF than mechanical pancreatic stump closure.This work was supported completely by a grant for medical research from the Catalan Surgery Society. Project PI20/00008, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European UnionPueyo-Périz, E.; Téllez-Marquès, C.; Radosevic, A.; Morató, O.; Visa, L.; Ilzarbe, L.; Berjano, E.... (2022). Radiofrequency-assisted transection of the pancreas vs stapler in distal pancreatectomy: a propensity score matched cohort analysis. Scientific Reports. 12(1):1-8. https://doi.org/10.1038/s41598-022-11583-01812

Genomic Evidence for Complex Domestication History of the Cultivated Tomato in Latin America

The process of plant domestication is often protracted, involving underexplored intermediate stages with important implications for the evolutionary trajectories of domestication traits. Previously, tomato domestication history has been thought to involve two major transitions: one from wild Solanum pimpinellifolium L. to a semidomesticated intermediate, S. lycopersicum L. var. cerasiforme (SLC) in South America, and a second transition from SLC to fully domesticated S. lycopersicum L. var. lycopersicum in Mesoamerica. In this study, we employ population genomic methods to reconstruct tomato domestication history, focusing on the evolutionary changes occurring in the intermediate stages. Our results suggest that the origin of SLC may predate domestication, and that many traits considered typical of cultivated tomatoes arose in South American SLC, but were lost or diminished once these partially domesticated forms spread northward. These traits were then likely reselected in a convergent fashion in the common cultivated tomato, prior to its expansion around the world. Based on these findings, we reveal complexities in the intermediate stage of tomato domestication and provide insight on trajectories of genes and phenotypes involved in tomato domestication syndrome. Our results also allow us to identify underexplored germplasm that harbors useful alleles for crop improvement

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups

Background and Objectives: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti‐HBc) prevents transfusion‐transmitted HBV infection but can lead to significant donor loss. As isolated anti‐HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti‐HBc testing and the representation of rare blood groups in anti‐HBc‐positive donors. Materials and Methods: Three hundred ninety‐seven HBV surface antigen‐negative and anti‐HBc initially reactive blood donor samples were tested by five different anti‐HBc assays. Results: Eighty percentage of samples reactive in Architect anti‐HBc assay were positive by the Murex assay and anti‐HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty‐eight percentage of anti‐HBc‐positive donors identified as minority ethnic groups compared with 11% representation in anti‐HBc‐negative donors (p < 0.0001); the frequency of the Ro blood group in anti‐HBc‐positive donors was 18 times higher in non‐white ethnic groups. Conclusion: Using two anti‐HBc assays effectively enabled the identification of HBV‐exposed and potentially infectious donors, their deferral and potential clinical follow‐up. However, the exclusion of confirmed anti‐HBc‐positive donors will still impact the supply of rare blood such as Ro

Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis

Background: Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. Methods: AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. Findings: AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours. Interpretation: sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis. Funding: This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya. © 2021 The Author(s

Interaction of eukaryotic translation initiation factor 4G with the nuclear cap-binding complex provides a link between nuclear and cytoplasmic functions of the m7 guanosine cap

In eukaryotes the majority of mRNAs have an m7G cap that is added cotranscriptionally and that plays an important role in many aspects of mRNA metabolism. The nuclear cap-binding complex (CBC; consisting of CBP20 and CBP80) mediates the stimulatory functions of the cap in pre-mRNA splicing, 3' end formation, and U snRNA export. As little is known about how nuclear CBC mediates the effects of the cap in higher eukaryotes, we have characterized proteins that interact with CBC in HeLa cell nuclear extracts as potential mediators of its function. Using cross-linking and coimmunoprecipitation, we show that eukaryotic translation initiation factor 4G (eIF4G), in addition to its function in the cytoplasm, is a nuclear CBC-interacting protein. We demonstrate that eIF4G interacts with CBC in vitro and that, in addition to its cytoplasmic localization, there is a significant nuclear pool of eIF4G in mammalian cells in vivo. Immunoprecipitation experiments suggest that, in contrast to the cytoplasmic pool, much of the nuclear eIF4G is not associated with eIF4E (translation cap binding protein of eIF4F) but is associated with CBC. While eIF4G stably associates with spliceosomes in vitro and shows close association with spliceosomal snRNPs and splicing factors in vivo, depletion studies show that it does not participate directly in the splicing reaction. Taken together the data indicate that nuclear eIF4G may be recruited to pre-mRNAs via its interaction with CBC and accompanies the mRNA to the cytoplasm, facilitating the switching of CBC for eIF4F. This may provide a mechanism to couple nuclear and cytoplasmic functions of the mRNA cap structure

Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab

Background: To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy. Methods: Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination. Results: The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5–6.6), 9.4 (95% CI, 8.5–10.6), and 14 months (95% CI, 11.8–16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3–8.1), 12.7 (95% CI, 11.3–14.3), and 18.3 months (95% CI, 14.6–24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591–0.631) and 0.673 (95% CI, 0.636–0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351). Conclusions: We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design