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The ocean plays a key role in modulating the climate of the Earth system (ES). At the present time it is also a major sink both for the carbon dioxide (CO2) released by human activities and for the excess heat driven by the resulting atmospheric greenhouse effect. Understanding the ocean's role in these processes is critical for model projections of future change and its potential impacts on human societies. A necessary first step in assessing the credibility of such future projections is an evaluation of their performance against the present state of the ocean. Here we use a range of observational fields to validate the physical and biogeochemical performance of the ocean component of UKESM1, a new Earth system model (ESM) for CMIP6 built upon the HadGEM3-GC3.1 physical climate model. Analysis focuses on the realism of the ocean's physical state and circulation, its key elemental cycles, and its marine productivity. UKESM1 generally performs well across a broad spectrum of properties, but it exhibits a number of notable biases. Physically, these include a global warm bias inherited from model spin-up, excess northern sea ice but insufficient southern sea ice and sluggish interior circulation. Biogeochemical biases found include shallow remineralization of sinking organic matter, excessive iron stress in regions such as the equatorial Pacific, and generally lower surface alkalinity that results in decreased surface and interior dissolved inorganic carbon (DIC) concentrations. The mechanisms driving these biases are explored to identify consequences for the behaviour of UKESM1 under future climate change scenarios and avenues for model improvement. Finally, across key biogeochemical properties, UKESM1 improves in performance relative to its CMIP5 precursor and performs well alongside its fellow members of the CMIP6 ensemble.

Abstract For simulations intended to study the influence of anthropogenic forcing on climate, temporal stability of the Earth's natural heat, freshwater, and biogeochemical budgets is critical. Achieving such coupled model equilibration is scientifically and computationally challenging. We describe the protocol used to spin‐up the UK Earth system model (UKESM1) with respect to preindustrial forcing for use in the sixth Coupled Model Intercomparison Project (CMIP6). Due to the high computational cost of UKESM1's atmospheric model, especially when running with interactive full chemistry and aerosols, spin‐up primarily used parallel configurations using only ocean/land components. For the ocean, the resulting spin‐up permitted the carbon and heat contents of the ocean's full volume to approach equilibrium over 5,000 years. On land, a spin‐up of 1,000 years brought UKESM1's dynamic vegetation and soil carbon reservoirs toward near‐equilibrium. The end‐states of these parallel ocean‐ and land‐only phases then initialized a multicentennial period of spin‐up with the full Earth system model, prior to this simulation continuing as the UKESM1 CMIP6 preindustrial control (piControl). The realism of the fully coupled spin‐up was assessed for a range of ocean and land properties, as was the degree of equilibration for key variables. Lessons drawn include the importance of consistent interface physics across ocean‐ and land‐only models and the coupled (parent) model, the extreme simulation duration required to approach equilibration targets, and the occurrence of significant regional land carbon drifts despite global‐scale equilibration. Overall, the UKESM1 spin‐up underscores the expense involved and argues in favor of future development of more efficient spin‐up techniques.

Most front-line tuberculosis drugs are ineffective against hypoxic non-replicating drug-tolerant Mycobacterium tuberculosis ( Mtb ) contributing to phenotypic antimicrobial resistance (AMR). This is largely due to the poor permeability in the thick and waxy cell wall of persister cells, leading to diminished drug accumulation and reduced drug-target engagement. Here, using an "arm-to-disarm" prodrug approach, we demonstrate that non-replicating Mtb persisters can be sensitized to Moxifloxacin (MXF), a front-line TB drug. We design and develop a series of nitroheteroaryl MXF prodrugs that are substrates for bacterial nitroreductases (NTR), a class of enzymes that are over-expressed in hypoxic Mtb . Enzymatic activation involves electron-transfer to the nitroheteroaryl compound followed by protonation via water that contributes to the rapid cleavage rate of the protective group by NTR to produce the active drug. Phenotypic and genotypic data are fully consistent with MXF-driven lethality of the prodrug in Mtb with the protective group being a relatively innocuous bystander. The prodrug increased intracellular concentrations of MXF than MXF alone and is more lethal than MXF in non-replicating persisters. Hence, arming drugs to improve permeability, accumulation and drug-target engagement is a new therapeutic paradigm to disarm phenotypic AMR.

Background: Microbiota composition is fundamental to human health with the intestinal microbiota undergoing critical changes within the first two years of life. The developing intestinal microbiota is shaped by maternal seeding, breast milk and its complex constituents, other nutrients, and the environment. Understanding microbiota-dependent pathologies requires a profound understanding of the early development of the healthy infant microbiota., Methods: Two hundred and fifty healthy pregnant women (≥20 weeks of gestation) from the greater Bern area will be enrolled at Bern University hospital's maternity department. Participants will be followed as mother-baby pairs at delivery, week(s) 1, 2, 6, 10, 14, 24, 36, 48, 96, and at years 5 and 10 after birth. Clinical parameters describing infant growth and development, morbidity, and allergic conditions as well as socio-economic, nutritional, and epidemiological data will be documented. Neuro-developmental outcomes and behavior will be assessed by child behavior checklists at and beyond 2 years of age. Maternal stool, milk, skin and vaginal swabs, infant stool, and skin swabs will be collected at enrolment and at follow-up visits. For the primary outcome, the trajectory of the infant intestinal microbiota will be characterized by 16S and metagenomic sequencing regarding composition, metabolic potential, and stability during the first 2 years of life. Secondary outcomes will assess the cellular and chemical composition of maternal milk, the impact of nutrition and environment on microbiota development, the maternal microbiome transfer at vaginal or caesarean birth and thereafter on the infant, and correlate parameters of microbiota and maternal milk on infant growth, development, health, and mental well-being., Discussion: The Bern birth cohort study will provide a detailed description and normal ranges of the trajectory of microbiota maturation in a high-resource setting. These data will be compared to data from low-resource settings such as from the Zimbabwe-College of Health-Sciences-Birth-Cohort study. Prospective bio-sampling and data collection will allow studying the association of the microbiota with common childhood conditions concerning allergies, obesity, neuro-developmental outcomes , and behaviour. Trial registration The trial has been registered at www., Clinicaltrials: gov , Identifier: NCT04447742., (© 2023. The Author(s).)

We observed the changes in the angular measurements commonly used in the evaluation of the first metatarsal and first metatarsophalangeal joint in cadaveric specimens before and after frontal plane rotation of the first metatarsal. Measurements of the first and second intermetatarsal angle (IMA), hallux abductus angle, proximal articular set angle, and tibial sesamoid position (TSP) were taken after varying degrees of varus and valgus rotation of the first metatarsal. Standard dorsoplantar radiographs were taken at 0°, 10°, 20°, and 30° of valgus rotation of the first metatarsal and repeated at 10°, 20°, and 30° varus rotation of the first metatarsal. The data were analyzed using a mixed linear model to compare the change in each angle measurement over the range of valgus and varus rotation. The change in the TSP was significant in both valgus and varus rotations (p = .0004 and p = .028, respectively), an increase in valgus rotation causing an increase in the TSP and an increase in varus rotation causing a decrease in TSP. The change in the IMA was significant compared with valgus rotation (p = .028), showing that as the valgus rotation increased, the IMA also increased. However, compared with the varus rotation, the correlation was not significant (p = .18). The proximal articular set angle and hallux abductus angle measurements, compared with metatarsal rotation, showed positive trends but were not statistically significant. From our results and a review of the published data, we have hypothesized that frontal plane rotation of the first metatarsal is an integral component of hallux abducto valgus pathologic features, specifically in relation to the TSP and IMA., (Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

The first intermetatarsal angle (IMA) is known to decrease after first metatarsophalangeal joint arthrodesis, although the exact mechanism by which this decrease occurs is not known. We measured the first IMA and obliquity of the medial cuneiform on anteroposterior weightbearing preoperative and postoperative radiographs in 86 feet and analyzed the statistical correlation between the IMA and the medial cuneiform angle. A change in the first IMA after first metatarsophalangeal joint fusion showed a strong positive correlation with a change in cuneiform obliquity (p < .0001). This finding was consistent in the direction and magnitude in each of 3 clinical subgroups: normal, p = .087; moderate deformity, p = .011; and severe deformity, p = .10. A comparison of the preoperative IMA and cuneiform obliquity revealed a trend toward a positive relationship but did not reach statistical significance (p = .08). The preoperative association between the IMA and medial cuneiform obliquity was not significant in any clinical subgroup, and the postoperative association between the IMA and cuneiform obliquity was not significant (p = .65). Clinical subgroup analysis showed no significant association between the IMA and the normal (p = .73) and moderately (p = .69) deformed feet, although the postoperative association between the IMA and cuneiform obliquity in the severely deformed group was significantly (p = .034) positive. A linear relationship between the reduction of the first IMA and medial cuneiform obliquity after metatarsophalangeal joint fusion was observed. Our findings suggest that frontal plane rotation influences cuneiform obliquity., (Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Rotation of the first metatarsal, as a component of hallux abducto valgus, is rarely discussed and is not addressed as a component of most hallux valgus corrective procedures. We believe frontal plane rotation of the first metatarsal to be an integral component of hallux abducto valgus deformity (the "third plane of deformity") and believe de-rotation is necessary for complete deformity correction. We observed the change in angular measurements commonly used in the evaluation of hallux valgus deformity in patients who underwent a modified lapidus procedure. We measured the intermetatarsal angle, hallux abductus angle, proximal articular set angle, and tibial sesamoid position on weightbearing radiographs of 25 feet in 24 patients who had undergone tarsal metatarsal corrective arthrodesis and lateral capsular release. Specific attention was given to reduction of the frontal plane rotation of the first metatarsal during correction. Our results showed a change in the angular measurements observed by 4 investigators as follows. The mean change in the intermetatarsal angle was 10.1° (p < .0001). The mean change in the hallux abductus angle was 17.8° (p < .0001). The mean change in the proximal articular set angle was 18.7° (p < .0001). The mean change in the tibial sesamoid position was 3.8 (p < .0001). Also, a consistent valgus, or everted position of the first metatarsal, was noted as a component of the hallux abducto valgus deformity in our patient population and was corrected by varus rotation or inversion of the metatarsal. We also reviewed the current literature related to anatomic changes in the first ray in the patient with hallux valgus deformity and reviewed our hypothesis regarding the reduction in the proximal articular set angle, which we believe to be related to frontal plane rotation of the first metatarsal, resulting in a radiographic artifact., (Copyright © 2013. Published by Elsevier Inc.)

Noise in an underground coal mine has dominant components generated mainly from 3 sources: (a) continuous mining machines, (b) roof bolters, and (c) cars/vehicles used to transport personnel and/or coal. Each of these 3 noise sources also has a number of well-defined sub-sources with their own noise characteristics. Sound level meters were used to collect noise data in the form of instantaneous readings and also to check calibration of other sound measuring instruments. The most useful information was obtained from a spectrum analysis of continuous digital recordings of noise over time. This paper discusses the variability or dynamics of generated noise in both frequency and time domains in relation to several independent variables related to coal extraction and transportation processes.

An analysis is presented of the range of secondary Swain-Schaad exponents to be expected at 25 degrees C in the absence of tunneling or kinetic complexity. From 15 996 sets of exact harmonic semiclassical equilibrium isotope effects for simple C-H/D/T exchange reactions and 954 sets of exact harmonic semiclassical secondary H/D/T kinetic isotope effects for C-H positions in simple organic reactions, the distribution of Swain-Schaad exponents versus magnitude of the isotope effect is determined. This distribution defines when a secondary Swain-Schaad exponent may be considered to implicate nonsemiclassical behavior, revises the expected Swain-Schaad exponent for extrapolation of secondary isotope effects, and serves as a guide to the uncertainty in such extrapolations.