Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis.

Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)-eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored.

Detecting life by behavior, the overlooked sensitivity of behavioral assays.

Detecting life has driven research and exploration for centuries, but recent attempts to compile and generate a framework that summarizes life features, aimed to develop strategies for life detection missions beyond planet Earth, have disregarded a key life feature: behavior. Yet, some behaviors such as biomineralization or motility have occasionally been proposed as biosignatures to detect life. Here, we capitalize on a specific taxis' motility behavior, magnetotaxis, to experimentally provide insights in support of behavior as an unambiguous, sensitive biosignature, and magnetic forces as a prescreening option.

First Simultaneous Measurement of Differential Muon-Neutrino Charged-Current Cross Sections on Argon for Final States with and without Protons Using MicroBooNE Data.

We report the first double-differential neutrino-argon cross section measurement made simultaneously for final states with and without protons for the inclusive muon neutrino charged-current interaction channel. The proton kinematics of this channel are further explored with a differential cross section measurement as a function of the leading proton's kinetic energy that extends across the detection threshold. These measurements use data collected with the MicroBooNE detector from 6.

First Search for Dark-Trident Processes Using the MicroBooNE Detector.

We present a first search for dark-trident scattering in a neutrino beam using a dataset corresponding to 7.2×10^{20} protons on target taken with the MicroBooNE detector at Fermilab. Proton interactions in the neutrino target at the main injector produce π^{0} and η mesons, which could decay into dark-matter (DM) particles mediated via a dark photon A^{'}.

First Measurement of η Meson Production in Neutrino Interactions on Argon with MicroBooNE.

We present a measurement of η production from neutrino interactions on argon with the MicroBooNE detector. The modeling of resonant neutrino interactions on argon is a critical aspect of the neutrino oscillation physics program being carried out by the DUNE and Short Baseline Neutrino programs. η production in neutrino interactions provides a powerful new probe of resonant interactions, complementary to pion channels, and is particularly suited to the study of higher-order resonances beyond the Δ(1232).

Search for Heavy Neutral Leptons in Electron-Positron and Neutral-Pion Final States with the MicroBooNE Detector.

We present the first search for heavy neutral leptons (HNLs) decaying into νe^{+}e^{-} or νπ^{0} final states in a liquid-argon time projection chamber using data collected with the MicroBooNE detector. The data were recorded synchronously with the NuMI neutrino beam from Fermilab's main injector corresponding to a total exposure of 7.01×10^{20} protons on target.

First Double-Differential Measurement of Kinematic Imbalance in Neutrino Interactions with the MicroBooNE Detector.

We report the first measurement of flux-integrated double-differential quasielasticlike neutrino-argon cross sections, which have been made using the Booster Neutrino Beam and the MicroBooNE detector at Fermi National Accelerator Laboratory. The data are presented as a function of kinematic imbalance variables which are sensitive to nuclear ground-state distributions and hadronic reinteraction processes. We find that the measured cross sections in different phase-space regions are sensitive to different nuclear effects.

First Measurement of Quasielastic Λ Baryon Production in Muon Antineutrino Interactions in the MicroBooNE Detector.

We present the first measurement of the cross section of Cabibbo-suppressed Λ baryon production, using data collected with the MicroBooNE detector when exposed to the neutrinos from the main injector beam at the Fermi National Accelerator Laboratory. The data analyzed correspond to 2.2×10^{20} protons on target running in neutrino mode, and 4.

Targeting the IGF-Axis in Cultured Pediatric High-Grade Glioma Cells Inhibits Cell Cycle Progression and Survival.

Pediatric high-grade gliomas (pHGG) accounts for approximately 8-12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9-15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined.

Enterococci in Diabetic Foot Infections: Prevalence, Clinical Characteristics, and Outcomes.

Background: Diabetic foot infections (DFIs) are frequently polymicrobial, yet the relevance of each isolated pathogen, remains ill-defined. Specifically, the prevalence and pathogenicity of enterococcal DFIs and the impact of targeted antienterococcal treatment remain elusive.

Methods: We collected demographic, clinical, and outcome-related data on patients admitted with DFIs to the Hadassah Medical Center diabetic foot unit between 2014 and 2019.

First Constraints on Light Sterile Neutrino Oscillations from Combined Appearance and Disappearance Searches with the MicroBooNE Detector.

We present a search for eV-scale sterile neutrino oscillations in the MicroBooNE liquid argon detector, simultaneously considering all possible appearance and disappearance effects within the 3+1 active-to-sterile neutrino oscillation framework. We analyze the neutrino candidate events for the recent measurements of charged-current ν_{e} and ν_{μ} interactions in the MicroBooNE detector, using data corresponding to an exposure of 6.37×10^{20} protons on target from the Fermilab booster neutrino beam.

Acute diabetic foot in post kidney transplantation patients receiving chronic immunosuppression-clinical presentation and outcomes.

Aims: Data regarding diabetic foot ulcers in patients after solid organ transplantation, particularly kidney transplantation, are limited. Chronic immunosuppression may be associated with impaired wound healing and a higher risk of amputations. In this study, we characterised the clinical presentation and outcomes of patients after kidney transplantation admitted to the diabetic foot unit, compared to non-kidney-transplant patients.

[HOSPITALIZATIONS DUE TO ACUTE DIABETIC FOOT: ANNUAL TRENDS AND PREDICTORS OF MORBIDITY AND MORTALITY - 5-YEARS EXPERIENCE OF A MULTIDISCIPLINARY UNIT].

Introduction: Since 2012, patients presenting to our hospital with an acute diabetic foot are hospitalized in a dedicated unit. This study describes patients' characteristics and trends in amputations, procedures and mortality during the years 2014-2018.

Methods: We retrospectively reviewed the electronic medical records of 694 patients admitted to the unit during the study period.

Predictors and outcomes of diabetic foot ulcer infection with ESBL-producing bacteria in a large tertiary center.

Objectives: The aim of this study was to describe the predictors and outcomes of infection with extended-spectrum beta-lactamase (ESBL)-producing bacteria in patients with an acute diabetic foot infection (DFI).

Methods: The records of patients admitted with acute DFI to a large tertiary hospital during the years 2014-2018 were reviewed. Demographic, clinical, and laboratory data were collected, as well as outcomes regarding amputations and mortality.

Identification of a Resistance Mechanism to IGF-IR Targeting in Human Triple Negative MDA-MB-231 Breast Cancer Cells.

Triple negative breast cancer (TNBC) is associated with unfavorable prognosis and high relapse rates following chemotherapy. There is an urgent need to develop effective targeted therapy for this BC subtype. The type I insulin-like growth factor receptor (IGF-IR) was identified as a potential target for BC management.

Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease.

Translational control of breast cancer plasticity.

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and "fate-switching" toward stem cell-like phenotypes.

Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression.

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation.

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis.

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer.

Analysis of the pathogenic I326T variant of human tRNA nucleotidyltransferase reveals reduced catalytic activity and thermal stability in vitro linked to a conformational change.

The I326T mutation in the TRNT1 gene encoding human tRNA nucleotidyltransferase (tRNA-NT) is linked to a relatively mild form of SIFD. Previous work indicated that the I326T variant was unable to incorporate AMP into tRNAs in vitro, however, expression of the mutant allele from a strong heterologous promoter supported in vivo CCA addition to both cytosolic and mitochondrial tRNAs in a yeast strain lacking tRNA-NT. To address this discrepancy, we determined the biochemical and biophysical characteristics of the I326T variant enzyme and the related variant, I326A.

Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.

There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations.

In vitro studies of disease-linked variants of human tRNA nucleotidyltransferase reveal decreased thermal stability and altered catalytic activity.

Mutations in the human TRNT1 gene encoding tRNA nucleotidyltransferase (tRNA-NT), an essential enzyme responsible for addition of the CCA (cytidine-cytidine-adenosine) sequence to the 3'-termini of tRNAs, have been linked to disease phenotypes including congenital sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD) or retinitis pigmentosa with erythrocyte microcytosis. The effects of these disease-linked mutations on the structure and function of tRNA-NT have not been explored. Here we use biochemical and biophysical approaches to study how five SIFD-linked amino acid substitutions (T154I, M158V, L166S, R190I and I223T), residing in the N-terminal head and neck domains of the enzyme, affect the structure and activity of human tRNA-NT in vitro.

Dysregulation of mRNA translation and energy metabolism in cancer.

Dysregulated mRNA translation and aberrant energy metabolism are frequent in cancer. Considering that mRNA translation is an energy demanding process, cancer cells must produce sufficient ATP to meet energy demand of hyperactive translational machinery. In recent years, the mammalian/mechanistic target of rapamycin (mTOR) emerged as a central regulatory node which coordinates energy consumption by the translation apparatus and ATP production in mitochondria.

The ability of an arginine to tryptophan substitution in Saccharomyces cerevisiae tRNA nucleotidyltransferase to alleviate a temperature-sensitive phenotype suggests a role for motif C in active site organization.

We report that the temperature-sensitive (ts) phenotype in Saccharomyces cerevisiae associated with a variant tRNA nucleotidyltransferase containing an amino acid substitution at position 189 results from a reduced ability to incorporate AMP and CMP into tRNAs. We show that this defect can be compensated for by a second-site suppressor converting residue arginine 64 to tryptophan. The R64W substitution does not alter the structure or thermal stability of the enzyme dramatically but restores catalytic activity in vitro and suppresses the ts phenotype in vivo.