Utility of systemic staging in breast cancer patients with a positive sentinel lymph node biopsy.

Background: CT thorax, abdomen and pelvis (CT-TAP) remains the standard in the identification of metastatic disease in patients with newly diagnosed breast cancer. In patients with proven micro and macro axillary nodal metastasis, the optimal radiological technique remains controversial. A consensus on which patients with axillary nodal disease should receive radiological staging for distant disease and how this should be performed is not currently available.

Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.

Aminoacyl-tRNA synthetases catalyze the ligation of a specific amino acid to its cognate tRNA. The resulting aminoacyl-tRNAs are indispensable intermediates in protein biosynthesis, facilitating the precise decoding of the genetic code. Pathogenic alleles in the aminoacyl-tRNA synthetases can lead to several dominant and recessive disorders.

Politics, policy and action: lessons from rural GP advocacy in Ireland.

Context: Ireland has one of the most rural populations in Europe. Rurality presents challenges when accessing health services but should not be perceived as problematic and in need of a structural fix. Structural urbanism where health care is viewed as a commodity for individuals, rather than an infrastructure for populations, innately favours larger urban populations and has detrimental outcomes for rural health.

Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease.

Aminoacyl-tRNA synthetases are indispensable enzymes in all cells, ensuring the correct pairing of amino acids to their cognate tRNAs to maintain translation fidelity. Autosomal dominant mutations V133F and Y330C in histidyl-tRNA synthetase (HARS) cause the genetic disorder Charcot-Marie-Tooth type 2W (CMT2W). Treatments are currently restricted to symptom relief, with no therapeutic available that targets the cause of disease.

Complex patterns of gene flow and convergence in the evolutionary history of the spiral-horned antelopes (Tragelaphini).

The Tragelaphini, also known as spiral-horned antelope, is a phenotypically diverse mammalian tribe comprising a single genus, Tragelaphus. The evolutionary history of this tribe has attracted the attention of taxonomists and molecular geneticists for decades because its diversity is characterised by conflicts between morphological and molecular data as well as between mitochondrial, nuclear and chromosomal DNA. These inconsistencies point to a complex history of ecological diversification, coupled by either phenotypic convergence or introgression.

Metabolic adaptation in epithelial ovarian cancer metastasis.

Epithelial ovarian cancer (EOC) is highly lethal due to its unique metastatic characteristics. EOC spheroids enter a non-proliferative state, with hypoxic cores and reduced oncogenic signaling, all of which contribute to tumour dormancy during metastasis. We investigated the metabolomic states of EOC cells progressing through the three steps to metastasis.

Mechanisms and Delivery of tRNA Therapeutics.

Transfer ribonucleic acid (tRNA) therapeutics will provide personalized and mutation specific medicines to treat human genetic diseases for which no cures currently exist. The tRNAs are a family of adaptor molecules that interpret the nucleic acid sequences in our genes into the amino acid sequences of proteins that dictate cell function. Humans encode more than 600 tRNA genes.

Delivery of AKT1 phospho-forms to human cells reveals differential substrate selectivity.

Protein kinase B (AKT1) is a serine/threonine kinase that regulates fundamental cellular processes, including cell survival, proliferation, and metabolism. AKT1 activity is controlled by two regulatory phosphorylation sites (Thr308, Ser473) that stimulate a downstream signaling cascade through phosphorylation of many target proteins. At either or both regulatory sites, hyperphosphorylation is associated with poor survival outcomes in many human cancers.

Mistranslating the genetic code with leucine in yeast and mammalian cells.

Translation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation.

Biosynthesis, Engineering, and Delivery of Selenoproteins.

Selenocysteine (Sec) was discovered as the 21st genetically encoded amino acid. In nature, site-directed incorporation of Sec into proteins requires specialized biosynthesis and recoding machinery that evolved distinctly in bacteria compared to archaea and eukaryotes. Many organisms, including higher plants and most fungi, lack the Sec-decoding trait.

Central Slip Repair using Trans-articular K-wires: A Comparative Study.

Central slip disruption may lead to PIP joint dysfunction causing significant morbidity. Existing evidence for any specific surgical management of these injuries is limited but does favor early mobilization of the PIP joint. To assess the functional outcome in a cohort of patients undergoing central slip repair with internal K-wire proximal interphalangeal joint splinting and complete immobilization against those with external splinting only.

Recoding UAG to selenocysteine in .

Unique chemical and physical properties are introduced by inserting selenocysteine (Sec) at specific sites within proteins. Recombinant and facile production of eukaryotic selenoproteins would benefit from a yeast expression system; however, the selenoprotein biosynthetic pathway was lost in the evolution of the kingdom Fungi as it diverged from its eukaryotic relatives. Based on our previous development of efficient selenoprotein production in bacteria, we designed a novel Sec biosynthesis pathway in using translation components.

Towards a Cure for HARS Disease.

Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNA). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific treatments are currently available.

Perseverance of protein homeostasis despite mistranslation of glycine codons with alanine.

By linking amino acids to their codon assignments, transfer RNAs (tRNAs) are essential for protein synthesis and translation fidelity. Some human tRNA variants cause amino acid mis-incorporation at a codon or set of codons. We recently found that a naturally occurring tRNA variant decodes phenylalanine codons with serine and inhibits protein synthesis.

Delivery of Active AKT1 to Human Cells.

Protein kinase B (AKT1) is a serine/threonine kinase and central transducer of cell survival pathways. Typical approaches to study AKT1 biology in cells rely on growth factor or insulin stimulation that activates AKT1 via phosphorylation at two key regulatory sites (Thr308, Ser473), yet cell stimulation also activates many other kinases. To produce cells with specific AKT1 activity, we developed a novel system to deliver active AKT1 to human cells.

Delivery of the selenoprotein thioredoxin reductase 1 to mammalian cells.

Over-expression of genetically encoded thioredoxin reductase 1 (TrxR1) TrxR1 can be toxic to cells due to the formation of a truncated version of the enzyme. We developed a new mammalian cell-based model to investigate TrxR1 activity. Fusion of the HIV-derived cell penetrating peptide (TAT) enabled efficient cellular uptake of purified TrxR1 containing 21 genetically encoded amino acids, including selenocysteine.

Ancestral archaea expanded the genetic code with pyrrolysine.

The pyrrolysyl-tRNA synthetase (PylRS) facilitates the cotranslational installation of the 22nd amino acid pyrrolysine. Owing to its tolerance for diverse amino acid substrates, and its orthogonality in multiple organisms, PylRS has emerged as a major route to install noncanonical amino acids into proteins in living cells. Recently, a novel class of PylRS enzymes was identified in a subset of methanogenic archaea.

Expanding codon size.

Engineering transfer RNAs to read codons consisting of four bases requires changes in tRNA that go beyond the anticodon sequence.

miRNA-Dependent Regulation of AKT1 Phosphorylation.

The phosphoinositide-3-kinase (PI3K)/AKT pathway regulates cell survival and is over-activated in most human cancers, including ovarian cancer. Following growth factor stimulation, AKT1 is activated by phosphorylation at T308 and S473. Disruption of the AKT1 signaling pathway is sufficient to inhibit the epithelial-mesenchymal transition in epithelial ovarian cancer (EOC) cells.

Do the frail experience more adverse events from intensive blood pressure control? A 2-year prospective study in the Irish Longitudinal Study on Ageing (TILDA).

Background: The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for management of hypertension in adults aged ≥65 years recommend a blood pressure (BP) treatment target of 130-139/70-79 mmHg if tolerated. Randomised controlled trials have advocated for lower BP, but this may have adverse outcomes in the frail. Yet, definitions of frailty vary.

A novel fluorescent reporter sensitive to serine mis-incorporation.

High-fidelity translation was considered a requirement for living cells. The frozen accident theory suggested that any deviation from the standard genetic code should result in the production of so much mis-made and non-functional proteins that cells cannot remain viable. Studies in bacterial, yeast, and mammalian cells show that significant levels of mistranslation (1-10% per codon) can be tolerated or even beneficial under conditions of oxidative stress.