How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites.

One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. () DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria.

Hospital to community in Wales: What is the value of optometrists playing a greater role in managing neovascular AMD and glaucoma in primary care?

Purpose: To evaluate the value of enhanced optometric services for managing neovascular age-related macular degeneration (nAMD) and glaucoma in primary care optometry services, instead of hospital eye services (HES).

Methods: Seven enhanced optometric service pathways in primary care in Wales were assessed with a mixed-methods approach: three for nAMD and four for glaucoma. The methods were a patient-related experience measure (PREM), a Realist Review and Evaluation involving both patients and staff, a discrete event simulation model estimating the economic impact of the pathways and a workforce survey of optometrists to gauge capability and capacity.

The Palaeobiology of Two Crown Group Cnidarians: and gen. et sp. nov. from the Ediacaran of Newfoundland, Canada.

The Ediacaran of eastern Newfoundland preserves the world's oldest known eumetazoan body fossils, as well as the earliest known record of fossilized muscular tissue. Re-examination of the holotype of the eight-armed in terms of its morphology, the arrangement of its muscle filament bundles, and hitherto undescribed aspects of its anatomy support its interpretation as a crown staurozoan. We also document several new fossils preserving muscle tissue with a different muscular architecture to , but with only four arms.

Hydrodynamic insights into the paleobiology of the Ediacaran rangeomorph .

The Ediacaran of Newfoundland preserves some of the oldest complex macroscopic communities, several of which are dominated by the fractal-like rangeomorph genus . Here we use computational fluid dynamics and a detailed reconstruction of to document for the first time hydrodynamic phenomena associated with this sediment-reclining organism and its rangeomorph elements that are relevant to interpreting feeding strategies, explain the recently documented rheotropic growth oblique to currents, and provide insights into their impact on the Ediacaran seafloor. Obliquely oriented are common, likely representing a compromise between maximized aspect ratio and minimization of drag.

Outcomes of the EMDataResource cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein-nucleic acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution.

CIME4R: Exploring iterative, AI-guided chemical reaction optimization campaigns in their parameter space.

Chemical reaction optimization (RO) is an iterative process that results in large, high-dimensional datasets. Current tools allow for only limited analysis and understanding of parameter spaces, making it hard for scientists to review or follow changes throughout the process. With the recent emergence of using artificial intelligence (AI) models to aid RO, another level of complexity has been added.

Earth's sinking surface.

China's major cities show considerable subsidence from human activities.

Disappearing cities on US coasts.

The sea level along the US coastlines is projected to rise by 0.25-0.3 m by 2050, increasing the probability of more destructive flooding and inundation in major cities.

Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution.

Current trends in macromolecular model refinement and validation.

The Guest Editors provide an introduction to the special issue of articles based on talks at the CCP4 Study Weekend 2022, which is available at https://journals.iucr.org/special_issues/2023/CCP42022/.

Neutron crystallographic refinement with REFMAC5 from the CCP4 suite.

Hydrogen (H) atoms are abundant in macromolecules and often play critical roles in enzyme catalysis, ligand-recognition processes and protein-protein interactions. However, their direct visualization by diffraction techniques is challenging. Macromolecular X-ray crystallography affords the localization of only the most ordered H atoms at (sub-)atomic resolution (around 1.

Coproduction of a resource sharing public views of health inequalities: An example of inclusive public and patient involvement and engagement.

Background: UNderstanding Factors that explain Avoidable hospital admission Inequalities-Research study (UNFAIR) addresses how to reduce health inequalities, particularly for avoidable hospital admissions. Our Patient and Public Involvement and Engagement (PPIE) members broached that health inequalities are complex, challenging to understand and communicate. They identified a need to explore diverse views, including people who have a higher risk of health inequalities.

Exploratory modelling of the impacts of sea-level rise on the Sundarbans mangrove forest, West Bengal, India.

In this paper we conduct exploratory simulations of the possible evolution of the Indian Sundarbans mangroves to 2100 under a range of future sea-level rise (SLR) scenarios, considering the effects of both inundation and shoreline erosion. The Sea Level Affecting Marshes Model (SLAMM) is used to simulate habitat transitions due to inundation and these outputs are combined with an empirical model of SLR-driven shoreline erosion. A set of plausible climate-induced SLR scenarios are considered, together with delta subsidence and constrained vertical sediment accretion.

Convolutional neural network framework for the automated analysis of transition metal X-ray photoelectron spectra.

X-ray photoelectron spectroscopy is an indispensable technique for the quantitative determination of sample composition and electronic structure in diverse research fields. Quantitative analysis of the phases present in XP spectra is usually conducted manually by means of empirical peak fitting performed by trained spectroscopists. However, with recent advancements in the usability and reliability of XPS instruments, ever more (inexperienced) users are creating increasingly large data sets that are harder to analyze by hand.

The CCP4 suite: integrative software for macromolecular crystallography.

The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces.

GEMMI and Servalcat restrain REFMAC5.

Macromolecular refinement uses experimental data together with prior chemical knowledge (usually digested into geometrical restraints) to optimally fit an atomic structural model into experimental data, while ensuring that the model is chemically plausible. In the CCP4 suite this chemical knowledge is stored in a Monomer Library, which comprises a set of restraint dictionaries. To use restraints in refinement, the model is analysed and template restraints from the dictionary are used to infer (i) restraints between concrete atoms and (ii) the positions of riding hydrogen atoms.

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones.

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in β-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.

Clonal haematopoiesis and risk of chronic liver disease.

Chronic liver disease is a major public health burden worldwide. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank).

Kinship practices in Early Iron Age southeast Europe: genetic and isotopic analysis of burials from the Dolge njive barrow cemetery, Dolenjska, Slovenia.

DNA analysis demonstrates that all seven individuals buried in an Early Iron Age barrow at Dolge njive, southeast Slovenia, are close biological relatives. Although group composition does not suggest strict adherence to a patrilineal or matrilineal kinship system, the funerary tradition appears highly gendered, with family links through both the male and female line being important in structuring communities. We explore the implications for our understandings of kinship and funerary practices in Early Iron Age southeast Europe.

Eliminating morbidity caused by neglected tropical diseases by 2030.

The objective of this manuscript is to provide selective examples of the work of the Pan American Health Organization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation.