UBR

Ubrogepant is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist which is used for the acute treatment of migraine in adults. The present study employs liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance spectroscopy (NMR) techniques for the identification and characterization of degradation impurities of ubrogepant. The forced degradation study of ubrogepant was performed as per the International Council for Harmonisation (ICH) Q1A and Q1B guidelines...

BACKGROUND: Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR)...

UBR4 is a 574 kDa E3 ligase (E3) of the N-degron pathway with roles in neurodevelopment, age-associated muscular atrophy and cancer. The catalytic module that carries out ubiquitin (Ub) transfer remains unknown. Here we identify and characterize a distinct E3 module within human UBR4 consisting of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2). The structure of an E2-E3 complex provides atomic-level insight into the specificity determinants of the hemiRING toward the cognate E2s UBE2A/UBE2B...

The N-end rule pathway is a proteolytic system involving the destabilization of N-terminal amino acids, known as N-degrons, which are recognized by N-recognins. Dysregulation of the N-end rule pathway results in the accumulation of undesired proteins, causing various diseases. The E3 ligases of the UBR subfamily recognize and degrade N-degrons through the ubiquitin-proteasome system. Herein, we investigated UBR4, which has a distinct mechanism for recognizing type-2 N-degrons. Structural analysis revealed that the UBR box of UBR4 differs from other UBR boxes in the N-degron binding sites...

Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay...

BACKGROUND AND OBJECTIVE: Despite the considerable progress achieved by U-Net-based models, medical image segmentation remains a challenging task due to complex backgrounds, irrelevant noises, and ambiguous boundaries. In this study, we present a novel approach called U-shaped Graph- and Transformer-guided Boundary Aware Network (GTBA-Net) to tackle these challenges. METHODS: GTBA-Net uses the pre-trained ResNet34 as its basic structure, and involves Global Feature Aggregation (GFA) modules for target localization, Graph-based Dynamic Feature Fusion (GDFF) modules for effective noise suppression, and Uncertainty-based Boundary Refinement (UBR) modules for accurate delineation of ambiguous boundaries...

Excitation/inhibition (E/I) balance is carefully maintained by the nervous system. The neurotransmitter GABA has been reported to be co-released with its sole precursor, the neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and glutamatergic signaling have not been fully elucidated. Caenorhabditis elegans DVB is an excitatory GABAergic motoneuron that drives the expulsion step in the defecation motor program. We show here that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter...

BACKGROUND: Ubiquitination controls almost all cellular processes. The dysregulation of ubiquitination signals is closely associated with the initiation and progression of multiple diseases. However, there is little comprehensive research on the interaction and potential function of ubiquitination regulators (UBRs) in spermatogenesis and cancer. METHODS: We systematically characterized the mRNA and protein expression of UBRs across tissues and further evaluated their roles in testicular development and spermatogenesis...

In the Arg/N-degron pathway, single N-terminal (Nt) residues function as N-degrons recognized by UBR box-containing N-recognins that induce substrate ubiquitination and proteasomal degradation. Recent studies led to the discovery of the autophagic Arg/N-degron pathway, in which the autophagic receptor p62/SQSTM1/Sequestosome-1 acts as an N-recognin that binds the Nt-Arg and other destabilizing residues as N-degrons. Upon binding to Nt-Arg, p62 undergoes self-polymerization associated with its cargoes, accelerating the macroautophagic delivery of p62-cargo complexes to autophagosomes leading to degradation by lysosomal hydrolases...

As defined by the N-degron pathway, single N-terminal (Nt) amino acids can function as N-degrons that induce the degradation of proteins and other biological materials. Central to this pathway is the selective recognition of N-degrons by cognate N-recognins that direct the substrates to either the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome pathway (ALP). Eukaryotic cells have developed diverse pathways to utilize all 20 amino acids in the genetic code as pro-N-degrons or N-degrons which can be generated through endoproteolytic cleavage or post-translational modifications...

Electroporation is a useful tool for the manipulation with the cell membrane permeability. Underlying physicochemical processes taking place at the molecular level during electroporation are relatively well studied. However, various processes remain unknown, one of them is lipid oxidation, a chain reaction that causes degradation of lipids, and might explain the long-lasting membrane permeability after the electric field has ceased. The aim of our study was to observe the differences in the electrical properties of planar lipid bilayers, as in vitro cell membrane models, due to lipid oxidation...

Centrosomes are essential parts of diverse cellular processes and precise regulation of the levels of their constituent proteins is critical for their function. One such protein is Pericentrin - PCNT in humans and PLP in Drosophila . Increased PCNT expression and its protein accumulation is linked to clinical conditions including cancer, mental disorders, and ciliopathies. However, the mechanisms by which PCNT levels are regulated remain underexplored. Our previous study (Galletta et al., 2020) demonstrated that PLP levels are sharply downregulated during early spermatogenesis and this regulation is essential to spatially position PLP on the proximal end of centrioles...

Diatoms are photosynthetic unicellular microalgae that drive global ecological phenomena in the biosphere and are emerging sustainable feedstock for an increasing number of industrial applications. Diatoms exhibit enormous taxonomic and genetic diversity, which often result in peculiar biochemical and biological traits. Transposable elements (TE) represent a substantial portion of diatom genomes and have been hypothesized to exert a relevant role in enriching genetic diversity and centrally contribute to genome evolution...

Characterizing and measuring the interactome of N-degrons and N-recognins are critical to the identification and verification of putative N-terminally arginylated native proteins and small-molecule chemicals that structurally and physiologically mimic the N-terminal arginine residue. This chapter focuses on in vitro and in vivo assays to confirm the putative interaction, and measure the binding affinity, between Nt-Arg-carrying natural (or Nt-Arg-mimicking synthetic) ligands and proteasomal or autophagic N-recognins carrying the UBR box or the ZZ domain...

The N-degron pathway is a degradative system in which single N-terminal (Nt) amino acids regulate the half-lives of proteins and other biological materials. These determinants, called N-degrons, are recognized by N-recognins that link them to the ubiquitin (Ub)-proteasome system (UPS) or autophagy-lysosome system (ALS). In the UPS, the Arg/N-degron pathway targets the Nt-arginine (Nt-Arg) and other N-degrons to assemble Lys48 (K48)-linked Ub chains by UBR box N-recognins for proteasomal proteolysis. In the ALS, Arg/N-degrons are recognized by the N-recognin p62/SQSTSM-1/Sequestosome-1 to induce cis-degradation of substrates and trans-degradation of various cargoes such as protein aggregates and subcellular organelles...

Parboiling is gaining increasing attention as it can enhance the head rice yield (HRY) and nutritional quality of non-pigmented rice. The traditional parboiling process with high-temperature immersion requires a long immersion period and results in hard texture of cooked parboiled black rice (PBR), which may be addressed by ultrasound-assisted immersion. In this study, we evaluated the effect of power, time and temperature of ultrasonic immersion on the HRY, texture profile and nutritional quality of PBR. Proper ultrasound-assisted immersion could increase the HRY by about 20% and the GABA content by up to 133%, as well as reduce the arsenic and cadmium content by up to 61% and 79% relative to untreated black rice (UBR), respectively...

Fermented products require metabolic enzymes from the microbial community for desired final products. Using a metatranscriptomic approach, the role of microorganisms in fermented products on producing compounds with a melanogenesis inhibition activity has not yet been reported. Previously, unpolished black rice (UBR) fermented with the E11 starter containing Saccharomyces cerevisiae, Saccharomycopsis fibuligera , Rhizopus oryzae , and Pediococcus pentosaceus (FUBR) showed potent melanogenesis inhibition activity...

SWItch/sucrose non-fermenting (SWI/SNF) complexes are a family of chromatin remodelers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here, we identify an alanine-to-valine-causing mutation in the SWI/SNF subunit snfc-5 ( SMARCB1 in humans) that prevents embryonic lethality in Caenorhabditis elegans nematodes harboring a loss-of-function mutation in the SWI/SNF subunit swsn-1 ( SMARCC1/2 in humans)...

BACKGROUND AND AIMS: Urinary bladder recurrences (UBRs) after radical nephroureterectomy (RNUx) are a known challenge in patients with upper-tract urothelial cancers (UTUCs). We aim to assess factors associated with UBR and clonal-relatedness with resected UTUC. METHODS: Patients who underwent RNUx for UTUC between 1998 and 2015 in five institutions were identified. Clonal relatedness between primary UTUC and subsequent UBR in a sub-cohort was assessed using next-generation sequencing...

Multimodal preoperative prehabilitation has been shown to be effective in improving the functional capacity of cancer patients, reducing postoperative complications and the length of hospital and ICU stay after surgery. The availability of prehabilitation units that gather all the professionals involved in patient care facilitates the development of integrated and patient-centered multimodal prehabilitation programs, as well as patient adherence. This article describes the process of creating a prehabilitation unit in our center and the role of perioperative nursing...