Rho1 and Rgf1 establish a new actin-dependent signal to determine growth poles in yeast independently of microtubules and the Tea1-Tea4 complex.

Cellular asymmetry begins with the selection of a discrete point on the cell surface that triggers Rho-GTPases activation and localized assembly of the cytoskeleton to establish new growth zones. The cylindrical shape of fission yeast is organized by microtubules (MT) that deliver the landmark Tea1-Tea4 complex at the cell tips to define the growth poles. However, only a few tea1Δ cells mistaken the direction of growth, indicating that they manage to detect their growth sites.

Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.

Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102.

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance.

Fission Yeast Rho1p-GEFs: From Polarity and Cell Wall Synthesis to Genome Stability.

Rho1p is a membrane-associated protein that belongs to the Rho family of small GTPases. These proteins coordinate processes such as actin remodelling and polarised secretion to maintain the shape and homeostasis of yeast cells. In response to extracellular stimuli, Rho1p undergoes conformational switching between a guanosine triphosphate (GTP)-bound active state and a guanosine diphosphate (GDP)-bound inactive state.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers.

An Advance Computing Numerical Heuristic of Nonlinear SIR Dengue Fever System Using the Morlet Wavelet Kernel.

This study is associated to solve the nonlinear SIR dengue fever system using a computational methodology by operating the neural networks based on the designed Morlet wavelet (MWNNs), global scheme as genetic algorithm (GA), and rapid local search scheme as interior-point algorithm (IPA), i.e., GA-IPA.

Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events.

Background & Aims: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD.

Methods: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort.

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization.

Competency of Neural Networks for the Numerical Treatment of Nonlinear Host-Vector-Predator Model.

The aim of this work is to introduce a stochastic solver based on the Levenberg-Marquardt backpropagation neural networks (LMBNNs) for the nonlinear host-vector-predator model. The nonlinear host-vector-predator model is dependent upon five classes, susceptible/infected populations of host plant, susceptible/infected vectors population, and population of predator. The numerical performances through the LMBNN solver are observed for three different types of the nonlinear host-vector-predator model using the authentication, testing, sample data, and training.

The Role of the Cell Integrity Pathway in Septum Assembly in Yeast.

Cytokinesis divides a mother cell into two daughter cells at the end of each cell cycle and proceeds via the assembly and constriction of a contractile actomyosin ring (CAR). Ring constriction promotes division furrow ingression, after sister chromatids are segregated to opposing sides of the cleavage plane. Cytokinesis contributes to genome integrity because the cells that fail to complete cytokinesis often reduplicate their chromosomes.

CAPPRIC Study-Characterization of Community-Acquired Pneumonia in Spanish Adults Managed in Primary Care Settings.

The real burden of community-acquired pneumonia (CAP) in non-hospitalized patients is largely unknown. This is a 3-year prospective, observational study of ambulatory CAP in adults, conducted in 24 Spanish primary care centers between 2016-2019. Sociodemographic and clinical variables of patients with radiographically confirmed CAP were collected.

Impact of liver injury on the severity of COVID-19: a systematic review with meta-analysis.

Background And Aims: SARS-CoV-2 is mainly a respiratory virus that has relevant systemic effects. We assessed the impact of baseline liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin) on COVID-19-related outcomes, including mortality, intensive care unit (ICU) admissions, and non-fatal severe complications.

Methods: after a systematic review of the relevant studies the odds ratio (OR), mean difference, sensitivity, specificity, and both positive and negative likelihood ratios were calculated for the prediction of relevant COVID-19 outcomes by performing a meta-analysis using fixed and random effects models.

Clinicopathological features of 214 maxillary sinus pathologies. A ten-year single-centre retrospective clinical study.

Background: Diagnosis of maxillary sinus pathology must include the clinical radiological study (CRS) and histopathological analysis. The aim of this study is 1) to describe the clinicopathological features of maxillary sinus lesions, obtained successively in a single medical centre over the last 10 years and 2) to determine the sensitivity and specificity for the diagnosis of malignant lesions based exclusively on the CRS.

Methods: It is a single-centre observational retrospective clinical study on patients who attended the University Hospital Complex of Santiago de Compostela (CHUS) with sinus pathologies during the period of 2009-2019.

Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner.

Actin-based tubular connections between cells have been observed in many cell types. Termed "tunneling nanotubes (TNTs)," "membrane nanotubes," "tumor microtubes (TMTs)," or "cytonemes," these protrusions interconnect cells in dynamic networks. Structural features in these protrusions vary between cellular systems, including tubule diameter and the presence of microtubules.

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease.

Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease.

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature.

Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction.

The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging.

Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo.

The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties.

Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas.

Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification.

Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists.

Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined.

Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects.

Methods: We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.

Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation.

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells.