Spontaneous base flipping helps drive Nsp15's preferences in double stranded RNA substrates.

Coronaviruses evade detection by the host immune system with the help of the endoribonuclease Nsp15, which regulates levels of viral double stranded RNA by cleaving 3' of uridine (U). While prior structural data shows that to cleave double stranded RNA, Nsp15's target U must be flipped out of the helix, it is not yet understood whether Nsp15 initiates flipping or captures spontaneously flipped bases. We address this gap by designing fluorinated double stranded RNA substrates that allow us to directly relate a U's sequence context to both its tendency to spontaneously flip and its susceptibility to cleavage by Nsp15.

The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD.

The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30 mg/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan.

Short- versus standard-course antimicrobial therapy for children with urinary tract infection: A meta-analysis.

Aim: To determine if short- (2-5 days) course antimicrobials are as effective as standard- (6-14 days) course antimicrobials in the treatment of symptomatic UTI in children.

Methods: MEDLINE and EMBASE were searched from their origin to January 2024. We only considered randomised controlled trials in children <18 years of age.

Associations of plasma extracellular microRNAs with new-onset breast cancer in the Framingham heart study.

Breast cancer is the second leading cause of cancer deaths among women. Multiple microRNAs (miRNAs) have been reported to be associated with breast cancer progression or metastasis. The purpose of the current study was to identify plasma extracellular miRNAs associated with incident breast cancer.

Accuracy of Screening Tests for the Diagnosis of Urinary Tract Infections in Young Children.

Background: The objective of this study was to compare the accuracy of available tests for pyuria, including newer automated tests, and to examine the implications of requiring them for the diagnosis of urinary tract infections (UTIs).

Methods: We included children between 1 and 36 months of age undergoing bladder catheterization for suspected UTIs who presented to 1 of 3 pediatric centers. Using a positive urine culture result as the reference standard, we compared the sensitivity of 5 modalities for assessing pyuria at the cutoffs most often used clinically for detecting children with a positive culture result: leukocyte esterase on a dipstick, white blood cell (WBC) count on manual microscopy with and without using a hemocytometer, automated WBC enumeration using flow cytometry, and automated WBC enumeration using digital imaging with particle recognition.