Discovery of (2,4)-4-(()-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.

Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor () that was potent but had low oral bioavailability in rat.

Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.

Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2.

Identification and application of quality elements, indicators, and criteria for assessment of impact on habitats in marine Natura 2000 areas.

The EU Habitat Directive adopted in 1992, requires member states of the European Union to protect species and habitats considered to be of 'Community Interest' and listed in annexes to the directive. The appropriate environmental assessment of "plans and projects" is an important part of the conservation process. Despite several amendments and guidelines supporting the implementation of the Habitat Directive, science based operational procedures, indicators, and impact criteria for assessing potential negative impacts on marine Natura 2000 areas are still lacking.

Low-Dose CT-derived Bronchial Parameters in Individuals with Healthy Lungs.

Background CT-derived bronchial parameters have been linked to chronic obstructive pulmonary disease and asthma severity, but little is known about these parameters in healthy individuals. Purpose To investigate the distribution of bronchial parameters at low-dose CT in individuals with healthy lungs from a Dutch general population. Materials and Methods In this prospective study, low-dose chest CT performed between May 2017 and October 2022 were obtained from participants who had completed the second-round assessment of the prospective, longitudinal Imaging in Lifelines study.

Paracetamol overdose in Danish children and adolescents during the Covid-19 restrictions.

Introduction: To assess the effect of long-term isolation on the mental state of Danish youth. This study aimed to investigate trends in paracetamol overdoses among people under 18 years of age in Denmark during Covid-19 restrictions as an indicator of mental health.

Methods: All patients under the age of 18 years presenting with paracetamol overdose at one of the 18 paediatric departments in Denmark from 2016 to 2021 were included.

Metrics reloaded: recommendations for image analysis validation.

Increasing evidence shows that flaws in machine learning (ML) algorithm validation are an underestimated global problem. In biomedical image analysis, chosen performance metrics often do not reflect the domain interest, and thus fail to adequately measure scientific progress and hinder translation of ML techniques into practice. To overcome this, we created Metrics Reloaded, a comprehensive framework guiding researchers in the problem-aware selection of metrics.

Understanding metric-related pitfalls in image analysis validation.

Validation metrics are key for tracking scientific progress and bridging the current chasm between artificial intelligence research and its translation into practice. However, increasing evidence shows that, particularly in image analysis, metrics are often chosen inadequately. Although taking into account the individual strengths, weaknesses and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers.

HORTENSIA, a program package for the simulation of nonadiabatic autoionization dynamics in molecules.

We present a program package for the simulation of ultrafast vibration-induced autoionization dynamics in molecular anions in the manifold of the adiabatic anionic states and the discretized ionization continuum. This program, called HORTENSIA (Hopping Real-time Trajectories for Electron-ejection by Nonadiabatic Self-Ionization in Anions), is based on the nonadiabatic surface-hopping methodology, wherein nuclei are propagated as an ensemble along classical trajectories in the quantum-mechanical potential created by the electronic density of the molecular system. The electronic Schrödinger equation is numerically integrated along the trajectory, providing the time evolution of electronic state coefficients, from which switching probabilities into discrete electronic states are determined.

Chiroptical Properties of Planar Benzobisthiazole-Bridged Squaraine Dimers.

Five chiral squaraine dimers were synthesized by fusing chiral indolenine semisquaraines with three different benzobisthiazole bridges. The thereby created squaraine dimers show a strong splitting of the lowest energy absorption bands caused by exciton coupling. The intensities of the two exciton transitions and the energetic splitting depend on the angle of the two squaraine moieties within the chromophore dimer.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1.

Impact of COVID-19 Restrictions on Acute Gastroenteritis in Children: A Regional, Danish, Register-Based Study.

This study aimed to evaluate the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) restrictions such as social distancing on the occurrence of acute gastroenteritis (AGE) among children. This study is a register-based study, including every child seen in the departments of paediatrics with the initial diagnosis of AGE in three neighbouring hospitals in Denmark, from March 2018 through February 2021. The study also included every positive stool sample for AGE-causing pathogens analysed in these three hospitals from children during the same period.

Reproducibility of a combined artificial intelligence and optimal-surface graph-cut method to automate bronchial parameter extraction.

Objectives: Computed tomography (CT)-based bronchial parameters correlate with disease status. Segmentation and measurement of the bronchial lumen and walls usually require significant manpower. We evaluate the reproducibility of a deep learning and optimal-surface graph-cut method to automatically segment the airway lumen and wall, and calculate bronchial parameters.

Conditioned Media from Head and Neck Cancer Cell Lines and Serum Samples from Head and Neck Cancer Patients Drive Catabolic Pathways in Cultured Muscle Cells.

Background: The role of secreted factors from the tumor cells in driving cancer cachexia and especially muscle loss is unknown. We wanted to study both the action of secreted factors from head and neck cancer (HNC) cell lines and circulating factors in HNC patients on skeletal muscle protein catabolism.

Methods: Conditioned media (CM) made from head and neck cancer cell lines and mix of sera from head and neck cancer (HNC) patients were incubated for 48 h with human myotubes.

Time-resolved photoelectron spectroscopy of 4-(dimethylamino)benzethyne - an experimental and computational study.

We investigated the excited-state dynamics of 4-(dimethylamino)benzethyne (4-DMABE) in a combined theoretical and experimental study using surface-hopping simulations and time-resolved ionisation experiments. The simulations predict a decay of the initially excited S state into the S state in only a few femtoseconds, inducing a subsequent partial twist of the dimethylamino group within ∼100 fs. This leads to drastically reduced Franck-Condon factors for the ionisation transition to the cationic ground state, thus inhibiting the effective ionisation of the molecule, which leads to a vanishing photoelectron signal on a similar timescale as observed in our time-resolved photoelectron spectra.

Understanding metric-related pitfalls in image analysis validation.

Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers.

Prevalence and Burden of Migraine in Switzerland: Cross-Sectional Study in ten Specialised Headache Centres from the BECOME Study.

Introduction: There is limited real-world evidence on the burden of migraine among patients with prior preventive treatment failure (PPTF). In the BECOME Swiss subanalysis, we aimed to assess current prevalence of PPTF in patients with migraine seen at specialised headache centres in Switzerland and burden of migraine in these patients. Furthermore, we assessed this burden in subgroups stratified by monthly migraine days (MMDs) and number of PPTFs.

European coastal monitoring programmes may fail to identify impacts on benthic macrofauna caused by bottom trawling.

Bottom trawling (hereafter trawling) is the dominant human pressure impacting continental shelves globally. However, due to ongoing data deficiencies for smaller coastal vessels, the effects of trawling on nearshore seabed ecosystems are poorly understood. In Europe, the Water Framework Directive (WFD) provides a framework for the protection and improvement of coastal water bodies.

Symptomatic malaria enhances protection from reinfection with homologous parasites.

A signature remains elusive of naturally-acquired immunity against . We identified in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with a reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.

Quantum-classical dynamics of vibration-induced autoionization in molecules.

We present a novel method for the simulation of the vibration-induced autoionization dynamics in molecular anions in the framework of the quantum-classical surface hopping approach. Classical trajectories starting from quantum initial conditions are propagated on a quantum-mechanical potential energy surface while allowing for autoionization through transitions into discretized continuum states. These transitions are induced by the couplings between the electronic states of the bound anionic system and the electron-detached system composed of the neutral molecule and the free electron.

Telestration with augmented reality improves surgical performance through gaze guidance.

Background: In minimally invasive surgery (MIS), trainees need to learn how to interpret the operative field displayed on the laparoscopic screen. Experts currently guide trainees mainly verbally during laparoscopic procedures. A newly developed telestration system with augmented reality (iSurgeon) allows the instructor to display hand gestures in real-time on the laparoscopic screen in augmented reality to provide visual expert guidance (telestration).

Interfractional dose accumulation for MR-guided liver SBRT: Variation among algorithms is highly patient- and fraction-dependent.

Background And Purpose: Daily plan adaptations could take the dose delivered in previous fractions into account. Due to high dose delivered per fraction, low number of fractions, steep dose gradients, and large interfractional organ deformations, this might be particularly important for liver SBRT. This study investigates inter-algorithm variation of interfractional dose accumulation for MR-guided liver SBRT.

The Liver Tumor Segmentation Benchmark (LiTS).

In this work, we report the set-up and results of the Liver Tumor Segmentation Benchmark (LiTS), which was organized in conjunction with the IEEE International Symposium on Biomedical Imaging (ISBI) 2017 and the International Conferences on Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2017 and 2018. The image dataset is diverse and contains primary and secondary tumors with varied sizes and appearances with various lesion-to-background levels (hyper-/hypo-dense), created in collaboration with seven hospitals and research institutions. Seventy-five submitted liver and liver tumor segmentation algorithms were trained on a set of 131 computed tomography (CT) volumes and were tested on 70 unseen test images acquired from different patients.