Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex.

The phosphoribosyl pyrophosphate synthetase (PRPS) enzyme conducts a chokepoint reaction connecting central carbon metabolism and nucleotide production pathways, making it essential for life. Here, we show that the presence of multiple PRPS-encoding genes is a hallmark trait of eukaryotes, and we trace the evolutionary origins and define the individual functions of each of the five mammalian PRPS homologs - three isozymes (one testis-restricted) and two non-enzymatic associated proteins (APs) - which we demonstrate operate together as a large molecular weight complex capable of attaining a heterogeneous array of functional multimeric configurations. Employing a repertoire of isogenic fibroblast clones in all viable individual or combinatorial assembly states, we define preferential interactions between subunits, and we show that cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity.

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC.

Creation of de novo cryptic splicing for ALS/FTD precision medicine.

A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence.

Sectioning and Counting of Motor Neurons in the L3 to L6 Region of the Adult Mouse Spinal Cord.

Histology is the study of the microscopic structure of tissues. This protocol permits the generation of frozen transverse sections of lumbar spinal cord regions L3 to L6. It enables counting of murine ventral horn lumbar motor neurons in a reproducible manner.

Understanding and Measuring the Wellbeing of Carers of People With Dementia.

Background And Objectives: To determine how the wellbeing of carers of people with dementia is understood and measured in contemporary health research.

Research Design And Methods: A systematic review of reviews was designed, registered with PROSPERO, and then conducted. This focused on systematic reviews of research literature published from 2010 onwards; with the wellbeing of carers of people with dementia being a primary focus.

Women's experiences of infertility - towards a relational model of care.

Aims And Objectives: To consider the effectiveness of current models of patient-centred infertility care.

Background: Patient centredness is defined as one of six key dimensions of quality of care. In the field of infertility, a new interaction model of patient-centred infertility care is proposed.

The effect of pain on hip and knee kinematics during running in females with chronic patellofemoral pain.

Purpose: Despite the growing recognition of the role of abnormal hip and knee mechanics in patellofemoral pain (PFP), few studies have assessed if or how these mechanics change when the person experiences pain while running. Therefore, the purpose of this study was to determine if the development of pain while running resulted in altered hip and knee kinematics in female runners with PFP as compared to healthy female runners.

Methods: Thirty female runners (15 PFP, 15 controls) participated in an instrumented gait analysis while running for 30 min at a self-selected pace.

Proximal and distal kinematics in female runners with patellofemoral pain.

Background: Female runners have a high incidence of developing patellofemoral pain. Abnormal mechanics are thought to be an important contributing factor to patellofemoral pain. However, the contribution of abnormal trunk, hip, and foot mechanics to the development of patellofemoral pain within this cohort remains elusive.

Versatile routes to selenoether functionalised tertiary phosphines.

New selenoether functionalised tertiary phosphines, based on aryl (2a, 2b) or alkyl (4) backbones, have been synthesised and characterised. P,Se-chelation has been achieved upon complexation to square-planar Pt(II) (3a) or Pd(II) (3b) metal centres. For 3a and 3b, weak non-covalent M.