Correction: Validation of the Strengths and Difficulties Questionnaire (SDQ) emotional subscale in assessing depression and anxiety across development.

[This corrects the article DOI: 10.1371/journal.pone.

Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1.

Environmental influences on the distribution and ecology of the fluke intermediate host : a systematic review.

is one of the most distributed intermediate hosts of across Europe, North Africa and South America. Therefore, understanding the environmental preferences of this species is vital for developing control strategies for fascioliasis and other trematodes such as . This systematic literature review evaluates the current understanding of the snail's environmental preferences to identify factors which might aid control and areas where further research is needed.

Simple Scaling as a Tool to Help Assess the Closure-Free / Versus Δ Curve in a Range of Materials.

Recent studies have proposed a simple formula, which is based on Elber's original approach to account for -ratio effects, for determining the crack closure-free Δ versus / curve from the measured -ratio-dependent Δ versus / curves. This approach, which is termed "Simple Scaling," has been shown to collapse the various -ratio-dependent curves onto a single curve. Indeed, this approach has been verified for a number of tests on metals, polymers, and a medium-entropy alloy.

Policy approaches to decarbonising the transport sector in Aotearoa New Zealand: modelling equity, population health, and health-system effects.

Background: Health co-benefits are a key potential advantage of transport decarbonisation policy. However, health effects will occur in the context of existing transport-health inequities and decarbonisation policies will themselves affect inequities. This research examines the effects of national decarbonisation pathways for transport on population health, health inequity, and health-system costs in Aotearoa New Zealand.

USAF Characteristic Approach: A Robust Tool for Predicting Fatigue Crack Growth under Various Underload Spectra.

This paper forms part of an ongoing investigation into the tools required in linear elastic fracture mechanics (LEFM) for evaluating the durability of components designed for limited life replacement. In this study, we demonstrate that the USAF 'Characteristic ' method, when combined with the Hartman-Schijve adaptation of the NASGRO crack growth formula, can predict the impact of underloads on the propagation of small cracks in aluminum alloy AA7050-T7451 with reasonable accuracy. The published versus Δ small crack growth curves associated with five specific underload spectra are examined.

Durability Analysis of Cold Spray Repairs: Phase I-Effect of Surface Grit Blasting.

This paper presents the results of an extensive investigation into the durability of cold spray repairs to corrosion damage in AA7075-T7351 aluminium alloy specimens where, prior to powder deposition, the surface preparation involved grit blasting. In this context, it is shown that the growth of small naturally occurring cracks in cold spray repairs to simulated corrosion damage can be accurately computed using the Hartman-Schijve crack growth equation in a fashion that is consistent with the requirements delineated in USAF Structures Bulletin EZ-SB-19-01, MIL-STD-1530D, and the US Joint Services Structural Guidelines JSSG2006. The relatively large variation in the / versus Δ curves associated with low values of / highlights the fact that, before any durability assessment of a cold spray repair to an operational airframe is attempted, it is first necessary to perform a sufficient number of tests so that the worst-case small crack growth curve needed to perform the mandated airworthiness certification analysis can be determined.

Modelling Fatigue Crack Growth in High-Density Polyethylene and Acrylonitrile Butadiene Styrene Polymers.

Prior studies into fatigue crack growth (FCG) in fibre-reinforced polymer composites have shown that the two methodologies of Simple-Scaling and the Hartman-Schijve crack growth equation, which is based on relating the FCG rate to the Schwalbe crack driving force, Δ, were able to account for differences observed in the measured delamination growth curves. The present paper reveals that these two approaches are also able to account for differences seen in plots of the rate of crack growth, , versus the range of the imposed stress intensity factor, Δ, associated with fatigue tests on different grades of high-density polyethylene (HDPE) polymers, before and after electron-beam irradiation, and for tests conducted at different ratios. Also, these studies are successfully extended to consider FCG in an acrylonitrile butadiene styrene (ABS) polymer that is processed using both conventional injection moulding and additive-manufactured (AM) 3D printing.

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.

Trastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bearing mice carrying NCI-N87, Capan-1, JIMT-1, and MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T-DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response.

Lichen biomonitoring to assess spatial variability, potential sources and human health risks of polycyclic aromatic hydrocarbons (PAHs) and airborne metal concentrations in Manchester (UK).

Airborne metals and organic pollutants are linked to severe human health impacts, i.e. affecting the nervous system and being associated with cancer.

On Cyclic-Fatigue Crack Growth in Carbon-Fibre-Reinforced Epoxy-Polymer Composites.

The growth of cracks between plies, i.e., delamination, in continuous fibre polymer matrix composites under cyclic-fatigue loading in operational aircraft structures has always been a very important factor, which has the potential to significantly decrease the service life of such structures.

Supplementation of minerals and vitamins influences optimal targeted selective treatment thresholds for the control of gastro-intestinal nematodes in lambs.

Targeted Selective Treatment (TST) is a gastrointestinal nematode (GIN) control strategy where anthelmintic treatment decisions are made at an individual animal level. TST has been proven to reduce anthelmintic use and subsequently slow down anthelmintic resistance development, however questions remain regarding optimal TST methods and their applicability across farms. In this study, the influence of Mineral and Vitamin (MV) supplementation on optimal energy utilisation (EU) TST thresholds was assessed on three Welsh farms.

Production of volatile fatty acids by anaerobic digestion of biowastes: Techno-economic and life cycle assessments.

Production of volatile fatty acids from food waste and lignocellulosic materials has potential to avoid emissions from their production from petrochemicals and provide valuable feedstocks. Techno-economic and life cycle assessments of using food waste and grass to produce volatile fatty acids through anaerobic digestion have been conducted. Uncertainty and sensitivity analysis for both assessments were done to enable a robust forecast of key-aspects of the technology deployment at industrial scale.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer.

The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19.

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991.

The Epidemiology of Domain-Specific Physical Activity in New Zealand Adults: A Nationally Representative Cross-Sectional Survey.

Background: Surveillance of domain-specific physical activity (PA) helps to target interventions to promote PA. We examined the sociodemographic correlates of domain-specific PA in New Zealand adults.

Methods: A nationally representative sample of 13,887 adults completed the International PA Questionnaire-long form in 2019/20.