Search

The title phosphanegold(I) thiolate compound, [Au(C9H9N2O3S)(C21H21P)], is a second monoclinic polymorph (space group P21/c) that complements a previously reported Cc polymorph [Broker & Tiekink (2008). Acta Cryst. E64, m1582]. An SP donor set defines an approximately linear geometry about the gold atom in both forms. The key distinguishing feature between the present structure and the previously reported polymorph rests with the relative disposition of the thiolate ligand. In the title compound, the orientation is such to place the oxygen atom in close contact with the gold atom [Au...O = 2.915 (2) Å], in contrast to the aryl ring in the original polymorph. In the crystal, linear supramolecular chains along the a-axis direction mediated by C–H...π and nitro-O...π interactions are found. These pack with no directional interactions between them. The analysis of the Hirshfeld surfaces for both forms of [Au(C9H9N3O3S)(C21H21P)] indicates quite distinctive interaction profiles relating to the differences in intermolecular contacts found in their respective crystals.

Estrogen induces ERα-positive breast cancer aggressiveness via the promotion of cell proliferation and survival, the epithelial-mesenchymal transition, and stem-like properties. Integrin β4 signaling has been implicated in estrogen/ERα-induced tumorigenicity and anti-apoptosis; however, this signaling cascade poorly understood. ΔNp63, an N-terminally truncated isoform of the p63 transcription factor, functions as a transcription factor of integrinβ4 and therefore regulates cellular adhesion and survival. Therefore, the aim of the present study was to investigate the estrogen-induced interaction between ERα, ΔNp63 and integrin β4 in breast cancer cells. In ERα-positive MCF-7 cells, estrogen activated ERα transcription, which induced ΔNp63 expression. And ΔNp63 subsequently induced integrin β4 expression, which resulted in AKT phosphorylation and enhanced cell viability and motility. Conversely, there was no inductive effect of estrogen on ΔNp63-integrinβ4-AKT signaling or on cell viability and motility in ERα-negative MDA-MB-231 cells. ΔNp63 knockdown abolishes these estrogen-induced effects and reduces cell viability and motility in MCF-7 cells. Nevertheless, ΔNp63 knockdown also inhibited cell migration in MDA-MB-231 cells through reducing integrin β4 expression and AKT phosphorylation. In conclusion, estrogen enhances ERα-positive breast cancer cell viability and motility through activating the ERα-ΔNp63-integrin β4 signaling pathway to induce AKT phosphorylated activation. Those findings should be useful to elucidate the crosstalk between estrogen/ER signaling and ΔNp63 signaling and provide novel insights into the effects of estrogen on breast cancer progression.

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies., Competing Interests: Competing interests: J.H.H. and M.A.W. are former or current employees of Ideaya Biosciences and have an equity interest. T.I. is a member of the Ideaya Biosciences scientific advisory board and has an equity interest. T.I. is also a co-founder and member of the advisory board and has an equity interest in Data4Cure and Serinus Biosciences. The terms of these arrangements have been reviewed and approved by the UCSD in accordance with its conflict-of-interest policies. B.M.K. is an employee of Vividion Therapeutics and has equity interests in Pfizer and Vividion Therapeutics. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The peptidyl prolyl cis-trans isomerase Pin1 plays vital roles in diverse cellular processes and pathological conditions. NeuroD is a differentiation and survival factor for a subset of neurons and pancreatic endocrine cells. Although multiple phosphorylation events are known to be crucial for NeuroD function, their mechanisms remain elusive. In this study, we demonstrate that zebrafish embryos deficient in Pin1 displayed phenotypes resembling those associated with NeuroD depletion, characterized by defects in formation of mechanosensory hair cells. Furthermore, zebrafish Pin1 interacts with NeuroD in a phosphorylation-dependent manner. In Pin1-deficient cell lines, NeuroD is rapidly degraded. However, the protein stability of NeuroD is restored upon overexpression of Pin1. These findings suggest that Pin1 functionally regulates NeuroD protein levels by post-phosphorylation cis-trans isomerization during neuronal specification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Fong, Yang, Jiang, Korzh and Liou.)

Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs. While pairwise disruption of CDK4/6 is synthetic-lethal, only CDK6 is required for normal cell-cycle progression and transcriptional activation. Multiple CDKs (CDK1/7/9/12) are synthetic-lethal in combination with PRMT5, independent of cell-cycle control. In-depth analysis of mRNA expression and splicing patterns provides multiple lines of evidence that the CDK-PRMT5 dependency is due to aberrant transcriptional regulation resulting in premature termination. These inter-dependencies translate to drug-drug synergies, with therapeutic implications in cancer and other diseases., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Metastatic cutaneous lesions from colorectal in origin are extremely rare, and especially without any visceral metastasis. Due to its poor response to chemotherapy, it is a poor prognostic indicator with a 1-6 month(s) death rate. Routine screening colonoscopy should be highly encouraged. This case is about a patient with obstructing, bleeding right colon mass and metastatic cutaneous soft tissue mass postcolonic mass resection. The biology and the mechanism of these metastatic lesions are not well understood, and they can be mistaken with any other primary soft tissue malignancy., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2021.)

Oncogenesis relies on the alteration of multiple driver genes, but precisely which groups of alterations lead to cancer is not well understood. To chart these combinations, Zhao and colleagues use the CRISPR-Cas9 system to knockout all pairwise combinations among 52 tumor suppressor genes, with the goal of identifying groups of alterations that collaborate to promote cell growth. Interaction screens are performed across multiple models of tumorigenesis in cell cultures and mice, revealing clear cooperation among NF2 , PTEN , and TP53 in multiple models. These and other strongly synergistic interactions are characterized further by single-cell transcriptomic profiling. This methodology presents a scalable approach to move beyond single-gene drivers to map the complex gene networks that give rise to tumorigenesis. See related article by Zhao et al., p. 6090 ., (©2021 American Association for Cancer Research.)

Cell-line screens create expansive datasets for learning predictive markers of drug response, but these models do not readily translate to the clinic with its diverse contexts and limited data. In the present study, we apply a recently developed technique, few-shot machine learning, to train a versatile neural network model in cell lines that can be tuned to new contexts using few additional samples. The model quickly adapts when switching among different tissue types and in moving from cell-line models to clinical contexts, including patient-derived tumor cells and patient-derived xenografts. It can also be interpreted to identify the molecular features most important to a drug response, highlighting critical roles for RB1 and SMAD4 in the response to CDK inhibition and RNF8 and CHD4 in the response to ATM inhibition. The few-shot learning framework provides a bridge from the many samples surveyed in high-throughput screens ( n -of-many) to the distinctive contexts of individual patients ( n -of-one).

Most drugs entering clinical trials fail, often related to an incomplete understanding of the mechanisms governing drug response. Machine learning techniques hold immense promise for better drug response predictions, but most have not reached clinical practice due to their lack of interpretability and their focus on monotherapies. We address these challenges by developing DrugCell, an interpretable deep learning model of human cancer cells trained on the responses of 1,235 tumor cell lines to 684 drugs. Tumor genotypes induce states in cellular subsystems that are integrated with drug structure to predict response to therapy and, simultaneously, learn biological mechanisms underlying the drug response. DrugCell predictions are accurate in cell lines and also stratify clinical outcomes. Analysis of DrugCell mechanisms leads directly to the design of synergistic drug combinations, which we validate systematically by combinatorial CRISPR, drug-drug screening in vitro, and patient-derived xenografts. DrugCell provides a blueprint for constructing interpretable models for predictive medicine., Competing Interests: Declaration of Interests T.I. is a co-founder of Data4Cure, Inc., and has an equity interest. T.I. has an equity interest in Ideaya BioSciences, Inc. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We present an accessible, fast, and customizable network propagation system for pathway boosting and interpretation of genome-wide association studies. This system-NAGA (Network Assisted Genomic Association)-taps the NDEx biological network resource to gain access to thousands of protein networks and select those most relevant and performative for a specific association study. The method works efficiently, completing genome-wide analysis in under 5 minutes on a modern laptop computer. We show that NAGA recovers many known disease genes from analysis of schizophrenia genetic data, and it substantially boosts associations with previously unappreciated genes such as amyloid beta precursor. On this and seven other gene-disease association tasks, NAGA outperforms conventional approaches in recovery of known disease genes and replicability of results. Protein interactions associated with disease are visualized and annotated in Cytoscape, which, in addition to standard programmatic interfaces, allows for downstream analysis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Systems biology requires not only genome-scale data but also methods to integrate these data into interpretable models. Previously, we developed approaches that organize omics data into a structured hierarchy of cellular components and pathways, called a "data-driven ontology." Such hierarchies recapitulate known cellular subsystems and discover new ones. To broadly facilitate this type of modeling, we report the development of a software library called the Data-Driven Ontology Toolkit (DDOT), consisting of a Python package (https://github.com/idekerlab/ddot) to assemble and analyze ontologies and a web application (http://hiview.ucsd.edu) to visualize them. Using DDOT, we programmatically assemble a compendium of ontologies for 652 diseases by integrating gene-disease mappings with a gene similarity network derived from omics data. For example, the ontology for Fanconi anemia describes known and novel disease mechanisms in its hierarchy of 194 genes and 74 subsystems. DDOT provides an easy interface to share ontologies online at the Network Data Exchange., (Copyright © 2019. Published by Elsevier Inc.)

Background: The number of available reports regarding the influence of ethnicity on clinical features of allergic rhinitis (AR), especially disease severity in tropical climates, is limited. We aimed to compare clinical parameters and disease severity in AR patients of different ethnicities., Methods: Malay, Chinese, and Indian AR patients (n = 138) with confirmed sensitivity to Dermatophagoides pteronyssinus, Dematophagoides farinae, and Blomia tropicalis were tested for mite-specific immunoglobulin E (sIgE) levels. A detailed questionnaire was used to collect data on nasal symptom score (NSS), ocular symptom score (OSS), sum of symptoms score (SSS), quality of life score (QLS), symptomatic control score (SCS), and total sum of scores (TSS) and correlate the derived data with patients' demography, mite-polysensitivity, and sIgE levels., Results: AR-related symptoms were most severe in Malays and least in Chinese (p < 0.01). Age (r = 0.516 to 0.673, p < 0.05) and duration of AR (r = 0.635 to 0.726, p < 0.01) correlated positively with severity domains (NSS, SSS, QLS, and TSS) in Chinese. Duration of concurrent allergies was highest in Malays (p < 0.05). Polysensitivity predicted increased sIgE levels in Malays (r = 0.464 to 0.551, p < 0.01) and Indians (r = 0.541 to 0.645, p < 0.05) but affected NSS, SSS, and TSS only in Indians (r = 0.216 to 0.376, p < 0.05). sIgE levels were lowest among Chinese but correlated strongly with NSS, OSS, SSS, and TSS (r = 0408 to 0.898, p < 0.05)., Conclusion: Clinical parameters in AR may be influenced by race. Symptoms were most severe among Malays but did not correlate with other variables examined. Although Indian ethnicity did not impact disease severity, duration of concurrent allergies and mite-polysensitivity was associated with more severe disease. Age, duration of disease, and sIgE levels may be useful indicators of disease severity in Chinese., (© 2016 ARS-AAOA, LLC.)

para‑Phenylenediamine (p‑PD) is a potential carcinogen, and widely used in marketed hair dye formulations. In the present study, the role of the protein tyrosine kinase (PTK)/Ras/Raf/c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3k)/protein kinase B (Akt) pathways on the growth of NRK‑52E cells was investigated. The results demonstrated that p‑PD reduced cell viability in a dose‑dependent manner. The cell death due to apoptosis was confirmed by cell cycle analysis and an Annexin‑V‑fluorescein isothiocyanate binding assay. Subsequent to staining with 2',7'‑dichlorofluorescin diacetate, the treated cells demonstrated a significant increase in reactive oxygen species (ROS) generation compared with the controls. The effects of p‑PD on the signalling pathways were analysed by western blotting. p‑PD‑treated cells exhibited an upregulated phospho‑stress‑activated protein kinase/JNK protein expression level and downregulated Ras and Raf protein expression levels; however, Akt, Bcl‑2, Bcl‑XL and Bad protein expression levels were not significantly altered compared with the control. In conclusion, p‑PD induced apoptosis by a PTK/Ras/Raf/JNK‑dependent pathway and was independent of the PI3K/Akt pathway in NRK‑52E cells.

The yolk syncytial layer (YSL) performs multiple critical roles during zebrafish development. However, little is known about the cellular and molecular mechanisms that underlie the formation of this important extraembryonic structure. Here, we demonstrate by timelapse confocal microscopy of a transgenic line expressing membrane-targeted GFP that the YSL forms as a result of the absence of cytokinesis between daughter nuclei at the tenth mitotic division and the regression of pre-existing marginal cell membranes, thus converting the former margin of the blastoderm into a syncytium. We show that disruption of components of the cytoskeleton induces the formation of an expanded YSL, and identify Rock1 as the regulator of cytoskeletal dynamics that lead to YSL formation. Our results suggest that the YSL forms as a result of controlled cytokinesis failure in the marginal blastomeres, and Rock1 function is necessary for this process to occur. Uncovering the cellular and molecular mechanisms underlying zebrafish YSL formation offers significant insight into syncytial development in other tissues as well as in pathological conditions.

Background: The choroid plexus (ChP), a component of the blood-brain barrier (BBB), produces the cerebrospinal fluid (CSF) and as a result plays a role in (i) protecting and nurturing the brain as well as (ii) in coordinating neuronal migration during neurodevelopment. Until now ChP development was not analyzed in living vertebrates due to technical problems., Methodology/principal Findings: We have analyzed the formation of the fourth ventricle ChP of zebrafish in the GFP-tagged enhancer trap transgenic line SqET33-E20 (Gateways) by a combination of in vivo imaging, histology and mutant analysis. This process includes the formation of the tela choroidea (TC), the recruitment of cells from rhombic lips and, finally, the coalescence of TC resulting in formation of ChP. In Notch-deficient mib mutants the first phase of this process is affected with premature GFP expression, deficient cell recruitment into TC and abnormal patterning of ChP. In Hedgehog-deficient smu mutants the second phase of the ChP morphogenesis lacks cell recruitment and TC cells undergo apoptosis., Conclusions/significance: This study is the first to demonstrate the formation of ChP in vivo revealing a role of Notch and Hedgehog signalling pathways during different developmental phases of this process.

During gastrulation, optimal adhesion and receptivity to signalling cues are essential for cells to acquire new positions and identities via coordinated cell movements. T-box transcription factors and the Wnt signalling pathways are known to play important roles in these processes. Zebrafish tbx2b, a member of the TBX2 family, has previously been shown to be required for the specification of midline mesoderm. We show here that tbx2b transcripts are present during mid-gastrula before its expression is detected by whole-mount in situ hybridization. Isolated ectodermal cells deficient in Tbx2b have altered cell surface properties and the level of cadherins in these cells is lower. In chimaeric embryos generated by cell transplantation and single blastomere injections, Tbx2b-deficient cells are defective in cell movement in a cell-autonomous manner, resulting in their exclusion from the developing neural plate. Using this ;exclusion' phenotype as a screen, we show that Tbx2b acts within the context of Fz7 signalling. The exclusion of cells lacking T-box proteins in chimeras during development was demonstrated with other T-box genes and may indicate a general functional mechanism for T-box proteins.

The activation of the mitogen-activated protein (MAP) kinases by different environmental stresses has been previously observed in several dicot plant species. Here, we report the isolation of a novel MAP kinase in rice that is induced during infection by the blast fungus Magnaporthe grisea or upon mechanical wounding. The gene is designated as BWMK1 for blast- and wound-induced MAP kinase. The cDNA of BWMK1 was isolated from rice leaves challenged by the blast pathogen. Transcripts of the corresponding gene accumulated in rice leaves 4 h after blast inoculation and 30 min after mechanical wounding. This gene encodes a 506 amino acid protein that contains a new dual-phosphorylation activation motif TDY and about 150 unique amino acids on its C terminus. In-gel kinase activity and immunoprecipitation assays confirmed that BWMK1 is a functional MAP kinase. These results show that BWMK1 is a new member of the plant MAP kinase family and may mediate both defense and wound signaling in rice.

In situ gamma spectrometry is an efficient method for monitoring the progress of cleanup activities for radioactive contaminants in surface soil and for evaluating the attainment of cleanup standards. However, desired data precision and accuracy must be specified for such a detection system prior to the operation to ensure that the level of uncertainty associated with the concentration measurements is acceptable. A method for developing data quality objectives is described in this paper for in situ gamma spectrometry to achieve numerical goals for data precision and accuracy for cleanup operations. Concentration measurement for a radionuclide at its cleanup level must have a precision commensurate with the importance of cleanup decisions. The 95% lower limit of detection of the system is suggested to be about one tenth the expected system response at the cleanup level. The count time required to achieve the preferred 95% lower limit of detection, and hence the desired precision, can then be determined. The accuracy error arises from the overall calibration factor, which relates the detector responses (e.g., count rate) to physical quantities of interest (e.g., radionuclide soil concentration). The major source of error for the calibration factor using in situ gamma spectrometry is the misidentification of the type of the depth profile of radionuclide concentration in soil. If surrogate radionuclides are used, such as 241Am for plutonium, the variation in the concentration ratio would be another significant source of error. Soil sampling programs performed prior to a cleanup operation will greatly reduce the accuracy error for an in situ detection system, and the analysis of system errors may determine the degree of sampling required. The planning of such a program is discussed in the study. Uncertainty analysis using a Latin Hypercube sampling technique for the calibration factor is also demonstrated. The quantitative result of the uncertainty analysis is useful for determining a nuclide's maximum peak count rate using gamma spectrum that ensures the attainment of the cleanup standard for that nuclide with a pre-specified confidence level (e.g., 95%). The cleanup operation of 239,240Pu in surface soil in the safety shot areas at the Nevada Test Site serves as an example to illustrate the data quality objectives development.

In cleanup operations and environmental surveillance efforts, a level of concern usually specifies a concentration limit for a particular radionuclide above which some action may be warranted. It is critical that the analytical method selected for measurements has a detection limit well below the action level. This is to guarantee that the technique used provides precise assessment at the level of concern. Sample analysis made with good precision is one of the major steps for obtaining quality data that allow a sound decision on whether the nuclide concentration is in compliance. This paper examines how the magnitude of the detection limit of an analysis method affects the precision of a measurement at the action level. With the established relationship, the detection limit that would achieve a pre-set precision for measurements at a level of concern can be quantitatively determined. The desired detection capability thus serves as a guide for selecting the appropriate measurement system.