Accurate structure prediction of biomolecular interactions with AlphaFold 3.

The introduction of AlphaFold 2 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design. Here we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture that is capable of predicting the joint structure of complexes including proteins, nucleic acids, small molecules, ions and modified residues. The new AlphaFold model demonstrates substantially improved accuracy over many previous specialized tools: far greater accuracy for protein-ligand interactions compared with state-of-the-art docking tools, much higher accuracy for protein-nucleic acid interactions compared with nucleic-acid-specific predictors and substantially higher antibody-antigen prediction accuracy compared with AlphaFold-Multimer v.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

Background: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease.

Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer's disease brain.

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts.

A decade of arteriovenous fistula creations in the ⩾75 years population: Equal opportunity or sub-optimal use of resources.

Background: The optimal vascular access in the elderly remains contentious in the context of increasingly limited resources and anticipated survival on hemodialysis. Research focus has shifted to include the impact of vascular access on quality of life. This study explored clinical outcomes in individuals aged ⩾75 years who had an arteriovenous fistula (AVF) created in a single center over a 10-year period.

A cross-sectional survey of doctors' views on flexible postgraduate physician training in Ireland.

Recruitment and retention of doctors is a priority for the Irish healthcare service, with many leaving to work in regions with more favourable conditions. Aligning flexible training options with other jurisdictions may be an effective means of improving working conditions. We sought to assess possible improvements to the existing system and to review barriers to flexible training.

The quality of published paediatric audits and their standards.

Objective: Audit is a recognised tool for evaluating the performance and improving the quality of health services. In Ireland and the UK, clear resources are available outlining audit elements. This study was undertaken to evaluate paediatric audits published from 2007 to 2020 to determine the adherence level to the definition of audit and to assess the quality of audit standards.

Evaluation of the Quick Wee method of inducing faster clean catch urine collection in pre-continent infants: a randomized controlled trial.

Introduction: The acquisition of non-contaminated urine samples in pre-continent infants remains a challenge. The Quick Wee method uses bladder stimulation to induce voiding. A previous randomized trial showed a higher rate of voiding within 5 minutes using this method.

Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors.

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-]pyrimidine derivative as a moderate dual PI3K/PIM-1 inhibitor.

Adaptive Athlete Training Plan Generation: An intelligent control systems approach.

Objectives: The planning and control of team sport training activities is an extremely important aspect of athletic development and team performance. This research introduces a novel system which leverages techniques from the fields of control system theory and artificial intelligence to construct optimal future training plans when unexpected disturbances and deviations from a training plan goal occur.

Design: Simulation-based experimental design.

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.

PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition.

The early experience of doctors training in pediatrics: patient safety culture and the role and influence of the registrar.

Introduction: Postgraduate medical training incorporates education, both formal and informal, combined with clinical service. This study explored the early training experience of pediatricians in Ireland and its potential impact on patient safety.

Aim: We sought to identify factors that contribute to the patient safety experience of new entrant pediatric trainees.

IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment.

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system.

Impaired glymphatic function and clearance of tau in an Alzheimer's disease model.

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease.

Transcriptional Signatures of Tau and Amyloid Neuropathology.

Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions.

Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer.

The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K/AKT/mTOR signalling.

Seasonal Occurrence of Potato Psyllid () and Risk of Zebra Chip Pathogen () in Northwestern New Mexico.

Potato psyllid () is one of the most important pests in potatoes ( L.) due to its feeding behavior and the transmission of a bacterium ( Liberibacter solanacearum) that causes zebra chip disease, altering the quality of the potato tuber and the fried potato chip or french fry. This pest is thus a threat to the chip potato industry and often requires preventive measures including the use of costly insecticides.

Population Dynamics of Six Major Insect Pests During Multiple Crop Growing Seasons in Northwestern New Mexico.

This study was conducted to monitor the population dynamics of six major insect pests at the NMSU Agricultural Science Center at Farmington (ASC-Farmington) and within an adjacent commercial farm (Navajo Agricultural Products Industry, NAPI) for more effective and efficient pest management during the 2013-2019 period. Specific pheromone traps, sticky and net traps were used to collects moths of beet armyworm (), cabbage looper ( ), corn earworm (), fall armyworm (), potato psyllid (), and western bean cutworm (). These insects generally appear in early June and their population decreases toward the end of August/early September with different peak times and magnitudes during July and August.

Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid β (Aβ) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover.

Correction to: Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia.

In the original publication of this article [1], the funding acknowledgement for grant "Alzheimer Society Research Program (ASRP) from the Alzheimer Society of Canada" was missing.

Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.

The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor.

Use of a fluorinated probe to quantitatively monitor amino acid binding preferences of ruthenium(ii) arene complexes.

In order to address outstanding questions about ruthenium complexes in complex biological solutions, 19F NMR spectroscopy was used to follow the binding preferences between fluorinated RuII(η6-arene)(bipyridine) complexes and protected amino acids and glutathione. Reporting what ruthenium compounds bind to in complex environments has so far been restricted to relatively qualitative methods, such as mass spectrometry and X-ray spectroscopic methods; however, quantitative information on the species present in the solution phase cannot be inferred from these techniques. Furthermore, using 1H NMR, in water, to distinguish and monitor a number of different complex RuII(η6-arene) adducts forming is challenging.