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Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages.Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data.Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies.Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field. [ABSTRACT FROM AUTHOR]

Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. [ABSTRACT FROM AUTHOR]

Alpine ecosystems are globally at risk from climate change. We use the International Union for the Conservation of Nature ( IUCN) Red List Criteria for ecosystems to assess the risk of ecosystem collapse in Australian alpine snow patch herbfields. These ecosystems occur on both mainland Australia and Tasmania. They are restricted to steep, south-easterly slopes where snow pack persists well into the summer growing season. Consequently, they are rare, and have high conservation significance. We evaluated the risk of snow patch herbfield 'ecosystem collapse' against criteria that accounted for the ecosystem's restricted distribution, projected decline in the snowpack and increased rates of invasion by taller growing native species of shrub and grass. Our analyses revealed considerable uncertainty in estimates of risk based on some criteria, particularly those related to thresholds of ecosystem collapse caused by biotic change. On the basis of the IUCN Red List criteria, we conclude that the ecosystem is 'endangered'. This is because of the restricted geographical distribution of the ecosystem, a substantial and highly likely decline in the abundance of snow (the principal abiotic driver of the ecosystem), and the prospect of invasion of much of the ecosystem by taller growing native shrubs and grasses. Our case study demonstrates the utility of the Red List methodology for assessing risks to biodiversity in rare ecosystems where changes to both abiotic factors and the relative dominance of native species constitute major threats. Our findings indicate the importance of snow patch herbfields as refugia for dwarf alpine plant species in the face of climate change, the need for continued monitoring, the removal of feral animals from the Australian Alps and scenario planning. [ABSTRACT FROM AUTHOR]

Kerry Stott and Fiona Cassells review the literature on the subject of weight gain from a biopsychosocial perspective. They describe the physiological changes that occur in the hypothalamus of patients taking clozapine affecting appetite and look at the behavioural factors that can influence food choice. [ABSTRACT FROM AUTHOR]

Outlines the logic used in a knowledge-based sequencing system for a hot-dip coating line (HDCL). Steel sequencing/scheduling applications; Details on the knowledge-based sequencing system; Outline of original knowledge-based system logic; Enhancements to the system; Results and implementation.

In 1984, Bethlehem Steel Corporation installed a new ingot mold stripping facility at its Bethlehem Plant that is capable of handling taller ingots. In order to take maximum advantage of this new facility, we developed a two-phase, computer-based procedure for selecting optimal ingot and internal ingot mold dimensions. Phase I of this procedure generates feasible ingot and internal ingot mold dimensions consistent with both the new stripper's capability and with mill constraints. Phase II then uses a set covering approach to select the optimal ingot and internal ingot mold sizes from among the feasible sizes generated. After analyzing the model, we recommended six new rectangular mold sizes to replace seven existing sizes. To date, implementation of these new ingot and mold sizes is proceeding smoothly and realizing the projected cost reduction benefits. [ABSTRACT FROM AUTHOR]

Copyright of Weed Research is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cross and self pollen tubes were cultured in 'Victoria' plum flowers (Prunus domestica L.) at 5, 10, 15 and 20%deg;C. Pollen-tube lengths measured at intervals were fitted by S-shaped growth curves (logistic function) and the parameters of the curves used to derive a generalized model for pollen-tube growth based on accumulated temperatures. Above the threshold of 2.5°C, maximum growth rate was 0.34 mm per day-degree and the tubes reached half their final length at 16.6 day-degrees above 2.5°C. The model indicates that fertilization of plum flowers requires 16-20d at a constant temperature of 5°C after pollination, but only 3-4d at 15°C. Mathematical expressions based on the model are given for estimating pollen-tube penetration and growth rate from values of cumulated temperature since pollination, and for estimating the cumulated temperature necessary for pollen tubes to penetrate a given distance. Pollen-tube growth rates were the same in detached flowers, flowers attached to twigs, and flowers on young, grafted trees in pots. In detached flowers growth stopped before fertilization could occur, but some embryo sacs were fertilized in both the remaining treatments. Accurate pollen-tube growth assessments can therefore be made with detached flowers which are most convenient to use and can be accommodated in small incubators. Studies on fertilization, however, must use flowers on bulky and expensive grafted trees. [ABSTRACT FROM AUTHOR]

Copyright of Weed Research is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We describe a case of HIV/tuberculosis (TB) co-infection from KwaZulu-Natal, South Africa, characterised by drug resistance in both pathogens. The development of drug resistance was linked temporally to two periods of incarceration. This highlights the urgent need for improved integration of HIV/TB control strategies within prison health systems and within the broader public health framework. [ABSTRACT FROM AUTHOR]

Assessment of nitrogen (N) loss forms and pathways from farming systems is important for improved understanding of potential off-farm impacts on high value environmental assets. The objective of this study was to estimate N losses in different pathways in dairy systems across the range of climate, soil and farm management by using west Gippsland (Victoria, Australia) as case study area, and to characterise the sensitivity of the adopted model parameters. We combined the point scale models DairyMod and Howleaky to estimate dissolved N (DN) and particulate N (PN) loads in runoff, and N leaching (LN) in deep drainage from representative dairy farms in west Gippsland. Monte Carlo error propagation with Latin hypercube sampling was performed to identify sensitive model parameters and assess potential uncertainty in N load predictions. The combined model was capable of simulating climate-soil-animal-pasture management interactions and estimating DN, PN and LN at an annual scale; which were estimated at up to 18 kg-N ha −1 , 15 kg-N ha −1 and 312 kg-N ha −1 , respectively. The combined model demonstrated that more intensive feeding as mixed ration, and nutrient budgeting that takes into account the fertiliser equivalent of recycled nutrients can achieve an increase in milk production by up to 13% and a decrease in N loads by up to 31% compared to the intensive system in the case study catchment. Soil type and farm management explained much of the variability (up to 76%) observed in LN and DN loads, whereas climate and soil type had significant influence on PN loads (62–77%). Year-to-year variation, particularly under dry conditions had a marked influence on N loads. Soil N, vegetation cover, rooting depth and soil maximum drainage rate must be well characterised in order to reduce potentially high uncertainty in the estimation of N losses in heterogeneous catchments. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether the likelihood of hospital-acquired complications for older people in Australia differs by whether they have dementia., Study Design: Matched cohort study., Setting, Participants: People aged 60 years or older with dementia who were admitted to five public hospitals in the South Western Sydney Local Health District, New South Wales, 1 January 2010 to 31 December 2020, and people without dementia admitted during the same period, matched by age, sex, number of medical conditions, and presence of selected specific medical conditions, emergency admission status, history of falls, and admission from a nursing home., Main Outcome Measures: Hospital-acquired complications (falls, pressure injuries, delirium, pneumonia, venous thromboembolism, new incontinence, malnutrition, in-hospital death), by dementia status., Results: A total of 217 459 people aged 60 years or older were admitted to the five hospitals during the study period. The mean age of the 11 393 patients with dementia (83 years; standard deviation [SD], 7.5 years) was higher than that of the 206 065 patients without dementia (73 years; SD, 8.9 years), and the proportion of women slightly larger (55% v 50%). Median hospital length of stay was longer for people with dementia (nine days; interquartile range [IQR], 4-19 days) than for people without dementia (three days; IQR, 1-9 days), and the number of in-hospital deaths higher (768, 7% v 584, 5%). After propensity score-based matching, the risks of falls (odds ratio [OR], 4.7; 95% confidence interval [CI], 3.8-5.7), pressure injury (OR, 1.4; 95% CI, 1.1-1.8), delirium (OR, 2.4; 95% CI, 2.0-3.0), and pneumonia (OR, 1.3; 95% CI, 1.01-1.7) were higher for people with dementia than for those without dementia; differences between the two groups in the risks of venous thromboembolism, malnutrition, and incontinence were not statistically significant., Conclusions: Given the greater risk of many hospital-acquired complications for people with dementia, targeted models of person-centred care are needed to ensure the best outcomes for these patients., (© 2024 The Author(s). Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Enhanced rock weathering (ERW) has attracted considerable attention as a carbon dioxide removal (CDR) strategy. However, a reliable method for accurately measuring, monitoring, and verifying carbon dioxide (CO 2 ) removal, particularly under field conditions, remains elusive. Here we describe a method for installing soil monoliths in an in situ buried apparatus that allows collection of water draining through a soil, undisturbed by external environmental factors that may affect similar apparatus located above ground. The method provides a robust, cost-effective means of collecting, developing, and establishing soil monoliths, allowing through drainage soil water sample collection and analysis, and so facilitating estimation of ERW CO 2 removal. A 200 mm diameter polyvinyl chloride (PVC) pipe is inserted into the soil to extract intact monoliths from a site of interest, withdrawn and then fitted with a basal double socket coupling and end cap for leachate collection. It is buried to reproduce soil environmental conditions, and water is collected via a sampling tube to surface. Validity was confirmed through an experimental trial with 36 monoliths over 6 months. This method enables accurate chemical analysis of solute draining through the soil monolith, which can be used to validate models of ERW efficacy.•PVC pipes are inserted into the target soil and subsequently extracted to retrieve intact soil monoliths•PVC sockets, equipped with a mesh and a geotextile membrane in the middle to retain the collected intact soil monolith and prevent soil particle transport, are then attached to the PVC pipe•PVC caps, featuring a small drainage tube attached to its outer side, are used to collect the leachate at the bottom part of the system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier B.V.)

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 + cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5 + cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells., (© 2024. The Author(s).)

Broadening of signals from atoms at interfaces can often be a limiting factor in applying solution NMR to the structure determination of complexes. Common contributors to such problems include exchange between free and bound states and the increased molecular weight of complexes relative to the free components, but another cause that can be more difficult to deal with occurs when conformational dynamics within the interface takes place at an intermediate rate on the chemical shift timescale. In this work we show how a carefully chosen mutation in the protein HMG-D rescued such a situation, making possible high-resolution structure determination of its complex with a dA2 bulge DNA ligand designed to mimic a natural DNA bend, and thereby revealing a new spatial organization of the complex., (© 2024 Wiley‐VCH GmbH.)

Linker histones play an essential role in chromatin packaging by facilitating compaction of the 11-nm fiber of nucleosomal "beads on a string." The result is a heterogeneous condensed state with local properties that range from dynamic, irregular, and liquid-like to stable and regular structures (the 30-nm fiber), which in turn impact chromatin-dependent activities at a fundamental level. The properties of the condensed state depend on the type of linker histone, particularly on the highly disordered C-terminal tail, which is the most variable region of the protein, both between species, and within the various subtypes and cell-type specific variants of a given organism. We have developed an in vitro model system comprising linker histone tail and linker DNA, which although very minimal, displays surprisingly complex behavior, and is sufficient to model the known states of linker histone-condensed chromatin: disordered "fuzzy" complexes ("open" chromatin), dense liquid-like assemblies (dynamic condensates), and higher-order structures (organized 30-nm fibers). A crucial advantage of such a simple model is that it allows the study of the various condensed states by NMR, circular dichroism, and scattering methods. Moreover, it allows capture of the thermodynamics underpinning the transitions between states through calorimetry. We have leveraged this to rationalize the distinct condensing properties of linker histone subtypes and variants across species that are encoded by the amino acid content of their C-terminal tails. Three properties emerge as key to defining the condensed state: charge density, lysine/arginine ratio, and proline-free regions, and we evaluate each separately using a strategic mutagenesis approach., Competing Interests: Competing interests statement:The authors declare no competing interest.

α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology., (© 2024. The Author(s).)

The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum , the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics., Competing Interests: Competing interests statement:The authors declare no competing interest.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease resulting in irreversible scarring within the lungs. However, the lack of biomarkers that enable real-time assessment of disease activity remains a challenge in providing efficient clinical decision-making and optimal patient care in IPF. Fibronectin (FN) is highly expressed in fibroblastic foci of the IPF lung where active extracellular matrix (ECM) deposition occurs. Functional upstream domain (FUD) tightly binds the N-terminal 70-kilodalton domain of FN that is crucial for FN assembly. In this study, we first demonstrate the capacity of PEGylated FUD (PEG-FUD) to target FN deposition in human IPF tissue ex vivo. We subsequently radiolabeled PEG-FUD with 64 Cu and monitored its spatiotemporal biodistribution via μPET/CT imaging in mice using the bleomycin-induced model of pulmonary injury and fibrosis. We demonstrated [ 64 Cu]Cu-PEG-FUD uptake 3 and 11 days following bleomycin treatment, suggesting that radiolabeled PEG-FUD holds promise as an imaging probe in aiding the assessment of fibrotic lung disease activity.

Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Xyloglucan is an abundant polysaccharide in many primary cell walls and in the human diet. Decoration of its α-xylosyl sidechains with further sugars is critical for plant growth, even though the sugars themselves vary considerably between species. Plants in the Ericales order - prevalent in human diets - exhibit β1,2-linked xylosyl decorations. The biosynthetic enzymes responsible for adding these xylosyl decorations, as well as the hydrolases that remove them in the human gut, are unidentified. GT47 xyloglucan glycosyltransferase candidates were expressed in Arabidopsis and endo-xyloglucanase products from transgenic wall material were analysed by electrophoresis, mass spectrometry, and nuclear magnetic resonance (NMR) spectroscopy. The activities of gut bacterial hydrolases BoGH43A and BoGH43B on synthetic glycosides and xyloglucan oligosaccharides were measured by colorimetry and electrophoresis. CcXBT1 is a xyloglucan β-xylosyltransferase from coffee that can modify Arabidopsis xyloglucan and restore the growth of galactosyltransferase mutants. Related VmXST1 is a weakly active xyloglucan α-arabinofuranosyltransferase from cranberry. BoGH43A hydrolyses both α-arabinofuranosylated and β-xylosylated oligosaccharides. CcXBT1's presence in coffee and BoGH43A's promiscuity suggest that β-xylosylated xyloglucan is not only more widespread than thought, but might also nourish beneficial gut bacteria. The evolutionary instability of transferase specificity and lack of hydrolase specificity hint that, to enzymes, xylosides and arabinofuranosides are closely resemblant., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

The Mars 2020 Flight System comprises a Cruise Stage; Aeroshell; Entry, Descent, and Landing system; Perseverance rover; and the Ingenuity helicopter. The Perseverance rover was successfully delivered to Jezero Crater on February 18, 2021. Among its science objectives, Perseverance is meant to search for rocks that are capable of preserving chemical traces of ancient life, if it existed, and to core and cache rock and regolith samples. The Perseverance rover is gathering samples for potential return to Earth as part of a Mars Sample Return campaign. Thus, controlling the presence of Earth-sourced biological contamination is important to protect the integrity of the scientific results as well as to comply with international treaty and NASA requirements governing Planetary Protection prior to launch. An unprecedented campaign of sampling and environmental monitoring occurred, which resulted in over 16,000 biological samples collected throughout spacecraft assembly. Engineering design, microbial reduction measures, monitoring, and process controls enabled the mission to limit the total spore bioburden to 3.73 × 10 5 spores, which provided 25.4% margin against the required limit. Furthermore, the total spore bioburden of all landed hardware was 3.86 × 10 4 , which provided 87% margin against the required limit. This manuscript outlines the Planetary Protection implementation approach and verification methodologies applied to the Mars 2020 flight system and its surrounding environments.

Xylan is the most abundant non-cellulosic polysaccharide in grass cell walls, and it has important structural roles. The name glucuronoarabinoxylan (GAX) is used to describe this variable hemicellulose. It has a linear backbone of β-1,4-xylose (Xyl) residues that may be substituted with α-1,2-linked (4-O-methyl)-glucuronic acid (GlcA), α-1,3-linked arabinofuranose (Araf), and sometimes acetylation at the O-2 and/or O-3 positions. The role of these substitutions remains unclear, although there is increasing evidence that they affect the way xylan interacts with other cell wall components, particularly cellulose and lignin. Here, we used substitution-dependent endo-xylanase enzymes to investigate the variability of xylan substitution in grass culm cell walls. We show that there are at least three different types of xylan: (i) an arabinoxylan with evenly distributed Araf substitutions without GlcA (AXe); (ii) a glucuronoarabinoxylan with clustered GlcA modifications (GAXc); and (iii) a highly substituted glucuronoarabinoxylan (hsGAX). Immunolocalization of AXe and GAXc in Brachypodium distachyon culms revealed that these xylan types are not restricted to a few cell types but are instead widely detected in Brachypodium cell walls. We hypothesize that there are functionally specialized xylan types within the grass cell wall. The even substitutions of AXe may permit folding and binding on the surface of cellulose fibrils, whereas the more complex substitutions of the other xylans may support a role in the matrix and interaction with other cell wall components., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)