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Abstract Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combined saturation mutagenesis of the paired domain of PAX6 with a yeast one-hybrid (Y1H) assay in which expression of a PAX6-GAL4 fusion gene drives antibiotic resistance. We quantified binding of more than 2700 single amino-acid variants to two DNA sequence elements. Mutations in DNA-facing residues of the N-terminal subdomain and linker region were most detrimental, as were mutations to prolines and to negatively charged residues. Many variants caused sequence-specific molecular gain-of-function effects, including variants in position 71 that increased binding to the LE9 enhancer but decreased binding to a SELEX-derived binding site. In the absence of antibiotic selection, variants that retained DNA binding slowed yeast growth, likely because such variants perturbed the yeast transcriptome. Benchmarking against known patient variants and applying ACMG/AMP guidelines to variant classification, we obtained supporting-to-moderate evidence that 977 variants are likely pathogenic and 1306 are likely benign. Our analysis shows that most pathogenic mutations in the paired domain of PAX6 can be explained simply by the effects of these mutations on PAX6:DNA association, and establishes Y1H as a generalisable assay for the interpretation of variant effects in transcription factors.

Abstract Social stability risk assessment (SSRA) has become the mainstream policy instrument for assessing potential risks of large-scale development projects across all sectors in China. In this paper, fuzzy qualitative comparative analysis (fsQCA) is used to quantify the impact of SSRA policy on economic competitiveness across China’s 31 provinces using a SSRA policy dataset (2003–2020) and a provincial economic competitiveness dataset (2019–2020). QCA combines Boolean algebra and set theory to identify configurations of conditions that are necessary or sufficient for a given outcome. Rather than following the mainstream statistical method of developing a single causal model that best fits the data, QCA explores multiple concurrent causality. A typology of SSRA policies was developed to guide our analysis. The research concluded that to support high economic competitiveness within provinces, SSRA policies must be structured around solving social stability problems and addressing a specific industry issue (e.g., pollution) in a particular industry (e.g., resources). Policies that only include one of these factors or that focus on the performance of government officials were found to contribute to low economic competitiveness. Reorienting the focus of SSRA policies could support more rigorous risk assessments and enhance economic competitiveness, particularly in provinces that host large-scale development projects. These findings have implications for China’s policymakers given their dual objectives of driving economic reform while maintaining a harmonious society.

The mammalian plasma membrane is known to contain domains with varying lipid composition and biophysical properties. However, studying these membrane lipid domains presents challenges due to their predicted morphological similarity to the bulk membrane and their scale being below the classical resolution limit of optical microscopy. To address this, we combine the solvatochromic probe di-4-ANEPPDHQ, which reports on its biophysical environment through changes in its fluorescence emission, with spectrally resolved single-molecule localisation microscopy. The resulting data comprises nanometre-precision localisation coordinates and a generalised polarisation value related to the probe's environment – a marked point pattern. We introduce quantification algorithms based on topological data analysis (PLASMA) to detect and map nano-domains in this marked data, demonstrating their effectiveness in both artificial membranes and live cells. By leveraging environmentally sensitive fluorophores, multi-modal single molecule localisation microscopy, and advanced analysis methods, we achieve nanometre scale mapping of membrane properties and assess changes in response to external perturbation with methyl-β-cyclodextrin. This integrated methodology represents an integrated toolset for investigating marked point pattern data at nanometre spatial scales. Studying lipid nano-domains within the mammalian cell plasma membrane remains a very challenging task. Here, the authors use the solvatochromic probe di-4-ANEPPDHQ, which is sensitive to its biophysical environment, to map membrane nano-environments via single-molecule localisation microscopy. [ABSTRACT FROM AUTHOR]

Introduction: Influenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming. Objective: Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model. Method: Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 μg/kg/day, i.p.) at day 3 post-infection. Results: AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 −/− animals. In mice treated with LXA4 (50 μg/kg/day, i.p., days 3–6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice. Conclusion: Therefore, treatment with a lipoxin A4 analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza. [ABSTRACT FROM AUTHOR]

Innovation in image-guided procedures has been driven by advances in robotic Cone Beam Computed Tomography (CBCT) systems. A fundamental challenge for CBCT imaging is metal artifacts arising from surgical tools and implanted hardware. Here, we outline how two universal non-circular imaging orbits, optimized for metal artifact reduction, can be implemented in real-time on clinical robotic CBCT systems. Demonstrating potential clinical utility, the universal orbits were implemented during a pedicle screw cervical spine fixation and hip arthroplasty performed on a porcine and ovine cadaver respectively. In both procedures, the universal non-circular orbits noticeably reduced the metal artifacts surrounding the implanted orthopedic hardware, revealing anatomy and soft tissue obscured in current conventional CBCT imaging. This work represents a key step in clinically translating universal orbits, unlocking high quality in-room procedural verification to increase broader use of robotic CBCT systems and reduce the occurrence of secondary corrective surgeries. [ABSTRACT FROM AUTHOR]

Background: As the needs and curricula of surgical residencies evolve, recent studies have focused on identifying factors that may be related to faster and more efficient surgical skill acquisition, such as experience with playing video games, sports, and other dexterous activities. The aim of this study was to elucidate the relationship between instrumental musical experience and laparoscopic surgical skill performance as well as to provide an overview of the available literature on this topic. Methods: A query from database inception to January 2023 of the PubMed database for literature discussing the association of musical experience and surgical skills was conducted. One hundred and twelve publications were sorted for relevance, yielding 16 included studies. The details of these studies were organized in a table and further analyzed. Study participants answered several questions regarding their personal instrumental musical experience and rotated through two minimally invasive surgery (MIS) skills stations. Participants received a score for each station based on level of performance. Descriptive statistics as well as non-parametric analyses and Spearman's correlations were calculated when appropriate to determine any associations between musical experience and laparoscopic surgical skill performance. Results: One hundred individuals participated in the study. Fifty-one of the participants indicated that they played at least one musical instrument, and twelve (9.0%) of these individuals played more than one instrument. There was no statistically significant difference or correlation in scores between individuals that played an instrument and those that did not (p > 0.05). Playing a greater number of instruments did not significantly correlate with increased performance (p > 0.05). There was also no statistically significant difference or correlation in scores within the group that played instruments based on instrument type or number of years playing an instrument (p > 0.05). Conclusions: Experience playing musical instruments did not confer an advantage in MIS skills tested in the present study. [ABSTRACT FROM AUTHOR]

We report details of a proficiency testing (PT) scheme for laboratories undertaking the analysis of diesel engine particulates (DEP) collected on workplace air filter samples. Within this occupational hygiene setting, the established approach is to measure the elemental carbon (EC) content within DEP as a specific marker of workers' exposure to engine emissions. Measuring EC is undertaken in laboratories using combustion-based analysers. To date six, PT rounds have been completed with participation ranging between thirteen and twenty-three laboratories. In each round participants received four quartz fibre filter samples (plus blank filters) loaded with DEP with indicative EC mass loadings in the range 9–204 µg/filter. Round assigned values and standard deviation for performance assessment values were calculated by consensus from returned participant data following outlier removal. On this basis, it was determined that on average 81 % of the returned data was deemed satisfactory, i.e. returning a z (or z') score ≤ 2. The use of two operationally defined analytical protocols, namely NIOSH 5040 and EN 16909, now dominate but they give different EC values so the preparation of reference air filter samples with preordained EC values determined using both protocols for use in future interlaboratory comparisons is therefore recommended. [ABSTRACT FROM AUTHOR]

A summary of the working group discussions on proficiency testing (PT) and external quality assessment (EQA) held at the Eurachem proficiency testing Workshop, Windsor, during September 2023 is provided. The working groups covered a range of issues concerned with current practice and future directions: the revision of ISO/IEC 17043; guidance on different methods for setting the standard deviation for proficiency assessment; collusion or falsification of results in PT/EQA; comparison of synthetic versus real PT items; performance assessment in non-quantitative PT/EQA; and risk analysis approach for PT/EQA participation. The discussions at the working groups were aided by a keynote lecture given on each of the topics on the same day. Delegates from forty-five countries attended the workshop and this diversity of backgrounds was represented on each of the working groups, capturing a range of views and experience from around the world and from a number of different analytical measurement sectors. Most of the working group participants were PT/EQA providers, participants in PT/EQA schemes and representatives of national accreditation bodies, including technical assessors. In addition, delegates from academia, PT/EQA software developers and test kit manufacturers were also present. [ABSTRACT FROM AUTHOR]

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Respiratory complex I is pivotal for cellular energy conversion, harnessing energy from NADH:ubiquinone oxidoreduction to drive protons across energy-transducing membranes for ATP synthesis. Despite detailed structural information on complex I, its mechanism of catalysis remains elusive due to lack of accompanying functional data for comprehensive structure-function analyses. Here, we present the 2.3-Å resolution structure of complex I from the α-proteobacterium Paracoccus denitrificans, a close relative of the mitochondrial progenitor, in phospholipid-bilayer nanodiscs. Three eukaryotic-type supernumerary subunits (NDUFS4, NDUFS6 and NDUFA12) plus a novel L-isoaspartyl-O-methyltransferase are bound to the core complex. Importantly, the enzyme is in a single, homogeneous resting state that matches the closed, turnover-ready (active) state of mammalian complex I. Our structure reveals the elements that stabilise the closed state and completes P. denitrificans complex I as a unified platform for combining structure, function and genetics in mechanistic studies. Respiratory complex I is pivotal for cellular energy conversion. Here, the authors present the structure of complex I from the α-proteobacterium Paracoccus denitrificans, revealing the elements that stabilise the closed state and completing P. denitrificans complex I as a unified platform for combining structure, function and genetics in mechanistic studies. [ABSTRACT FROM AUTHOR]

Beta vulgaris L. is a root vegetable that is consumed mainly as a food additive. This study aimed to describe the protective effect of B. vulgaris on Fe2+-mediated oxidative liver damage through in vitro, ex vivo, and in silico studies to establish a strong rationale for its protective effect. To induce oxidative damage, we incubated the livers of healthy male rats with 0.1 mM FeSO4 to induce oxidative injury and coincubated them with an aqueous extract of B. vulgaris root (BVFE) (15–240 µg/mL). Induction of liver damage significantly (p <.05) decreased the levels of GSH, SOD, CAT, and ENTPDase activities, with a corresponding increase in MDA and NO levels and Na+/K+ ATPase, G6 Pase, and F-1,6-BPase enzyme activities. BVFE treatment (p <.05) reduced these levels and activities to almost normal levels, with the most prominent effects observed at 240 µg/mL BVFE. An HPLC investigation revealed sixteen compounds in BVFE, with quercetin being the most abundant. Chlorogenic acid and iso-orientation showed the highest binding affinities for G6 Pase and Na+/K + ATPase, respectively. These findings suggest that B. vulgaris can protect against Fe2+-mediated liver damage by suppressing oxidative stress and cholinergic and purinergic activities while regulating gluconeogenesis. Overall, the hepatoprotective activity of this extract might be driven by the synergistic effect of the identified compounds and their probable interactions with target proteins. [ABSTRACT FROM AUTHOR]

Multiomic profiling of single cells by sequencing is a powerful technique for investigating cellular diversity. Existing droplet-based microfluidic methods produce many cell-free droplets, underutilizing bead barcodes and reagents. Combinatorial indexing on microplates is more efficient for barcoding but labor-intensive. Here we present Overloading And unpacKing (OAK), which uses a droplet-based barcoding system for initial compartmentalization followed by a second aliquoting round to achieve combinatorial indexing. We demonstrate OAK's versatility with single-cell RNA sequencing as well as paired single-nucleus RNA sequencing and accessible chromatin profiling. We further showcase OAK's performance on complex samples, including differentiated bronchial epithelial cells and primary retinal tissue. Finally, we examine transcriptomic responses of over 400,000 melanoma cells to a RAF inhibitor, belvarafenib, discovering a rare resistant cell population (0.12%). OAK's ultra-high throughput, broad compatibility, high sensitivity, and simplified procedures make it a powerful tool for large-scale molecular analysis, even for rare cells. Single-cell sequencing approaches need to balance sensitivity, throughput and experimental complexity. Here the authors combine droplet-based microfluidics and combinatorial indexing to develop OAK, a versatile method for ultra-high throughput single-cell multiomic profiling. [ABSTRACT FROM AUTHOR]

Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2–4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.Early intermittent feeding of mice with a high-cholesterol Western-type diet accelerates atherosclerosis compared with late continuous exposure to the Western-type diet, despite similar cumulative circulating LDL-C levels. [ABSTRACT FROM AUTHOR]

Reductive dissolution of barium (Ba) sulfate in wetland soils may increase Ba bioavailability in the environment, yet no information is available regarding Ba remediation using biochar. This study investigated the effectiveness of sugarcane (Saccharum officinarum) straw biochar pyrolyzed at 350 °C (BC350), 550 °C (BC550), and 750 °C (BC750) in inhibiting barite dissolution and, consequently, Ba availability in a soil artificially spiked with barite and flooded for 365 days. Increasing pyrolysis temperature alters the carbon structure, and increases dehydration and depolymerization, resulting in more stable biochar that releases less DOC (8.6-fold decrease from BC350 to BC750). Additionally, high-temperature biochar (BC750) had 1.7 times higher carbon (C) content, 2.4 times higher ash content, and a 13.1 times greater specific surface area (SSA) than low-temperature biochar (BC350). Amending soil with BC750 increased pH but did not promote reducing conditions, and thus did not promote barite dissolution. Conversely, greater DOC in low-temperature biochar, particularly BC350, favored reducing conditions and increased barite dissolution by 23%, with BC550 also showing an 18% increase. This enhancement led to a greater pool of Ba sorbed into more labile exchangeable sites. In summary, pyrolysis temperature affects biochar attributes, which in turn influences the soil geochemical environment and Ba speciation. Low-temperature biochar (BC350) shows potential as an amendment to increase the bioavailable Ba pool in assisted remediation programs, such as biochar-assisted phytoremediation. Highlights: • Biochar pyrolysis temperature affected both redox potential and barite dissolution. • BC750 mitigated barite dissolution while modifying exchangeable sorption sites. • DOC release from low temperature biochar promoted barite reductive dissolution. • BC350 may enhance biochar-mediated phytoremediation applications. [ABSTRACT FROM AUTHOR]

Embedding precision medicine in paediatric oncology shows promise to have a positive impact on how children with cancer will be treated in the future. While there are a number of studies of precision medicine in childhood cancer, there is limited evidence available on the cost of implementing the related testing. This is the first Australian study that systematically measures the cost of using precision medicine in the care of high-risk childhood cancers, through the Zero Childhood Cancer Precision Medicine Programme. In 2021 Australian dollars, the estimated costs inclusive of genomic and preclinical testing were: (A) $12,743 per patient for access; (B) $14,262 per identification of molecular cause; and (C) $21,769 per MTB recommendation. The information gained supports the understanding of the cost of reporting clinically significant outcomes relevant to the biology of the tumour, diagnosis, prognosis and potentially improving clinical management for a child. [ABSTRACT FROM AUTHOR]

This study investigated the role of host traits, habitat, and sampling season on the prevalence and intensity of parasites in three species of platycephalid fishes. Three host species sampled were dusky flathead (Platycephalus fuscus, n = 3), blue-spotted flathead (Platycephalus caeruleopunctatus, n = 38), and tiger flathead (Platycephalus richardsoni, n = 59). A total of 14 metazoan parasite species were collected over 15 months, between July 2020 and September 2021. The parasites found included a chondracanthid copepod, adult hemiuroidean trematodes, cestode plerocercoids, larval and adult acanthocephalans, larval and adult nematodes, and an unknown species of helminth. General linear models were used to assess the relationship between host traits and sampling season with parasite infection intensity. The infection intensity of an unidentified plerocercoid species in P. caeruleopunctatus was found to be significantly associated with both sampling season and the interaction of host mass with sex. In P. richardsoni the infection intensity of the acanthocephalan, Corynosoma sp. was found to correlate with sampling season. The highest richness of parasite taxa was recorded from P. richardsoni, which may be due to the wide depth range of P. richardsoni, coupled with its generalist diet. [ABSTRACT FROM AUTHOR]

Sleep disorders are highly prevalent in chronic kidney disease (CKD) but are often under-recognized. Restless legs syndrome, which is common in CKD owing to issues with dopamine metabolism and is exacerbated by iron deficiency and uraemia, can lead to poor sleep quality and increased daytime fatigue. Insomnia is also prevalent in CKD, particularly in patients requiring dialysis, with increased sleep latency and sleep fragmentation being reported. The cause of insomnia in CKD is multifactorial — poor sleep habits and frequent napping during dialysis, uraemia, medications and mood disorders have all been suggested as potential contributing factors. Sleep apnoea and CKD are also now recognized as having a bi-directional relationship. Sleep apnoea is a risk factor for accelerated progression of CKD, and fluid overload, which is associated with kidney failure, can lead to both obstructive and central sleep apnoea. The presence of obstructive sleep apnoea in CKD can exacerbate the already heightened cardiovascular morbidity and mortality in these patients, as well as leading to daytime fatigue and reduced quality of life. Increased awareness, timely diagnosis and appropriate therapeutic interventions are essential to reduce the negative impact of sleep disorders in patients with kidney disease. In this Review, Owen Lyons discusses the diagnosis, epidemiology and pathophysiology of three sleep disorders that commonly affect patients with chronic kidney disease — restless legs syndrome, insomnia and sleep apnoea — and their impact on patient morbidity and mortality. Key points: Sleep disorders, such as sleep apnoea, restless legs syndrome and insomnia, are very common in patients with chronic kidney disease (CKD), and their presence can have a substantial impact on symptom burden (including poor sleep quality, daytime fatigue and sleepiness), morbidity and mortality. Various treatment options for restless legs syndrome in CKD, including cool dialysate, iron supplementation and gabapentin, can be effective in improving sleep quality and reducing daytime fatigue. Evidence to support the use of sedatives or sleeping medications in CKD is lacking, but cognitive behavioural therapy for insomnia can be effective to improve sleep quality and daytime functioning. Sleep apnoea and kidney disease have a bi-directional relationship; obstructive sleep apnoea is associated with an accelerated decline in estimated glomerular filtration rate, whereas hypervolaemia in kidney failure can lead to obstructive and central sleep apnoea. Intensification of kidney replacement therapy or fluid removal by ultrafiltration attenuates the severity of sleep apnoea in patients with kidney failure. [ABSTRACT FROM AUTHOR]

Seabirds are among the most threatened avian taxa. Effective seabird conservation requires an understanding of both seabird distributions and habitat usage. Species distribution models can help identify important areas for protection and manage threats to seabird populations. However, populations of the same species may differ in their response to the environment, reducing the transferability of such models. In addition, individual-level responses to habitat may vary both within and between animal populations. Atlantic Puffins (Fratercula arctica) are classed as vulnerable to global extinction and a UK red-listed bird of concern. Consequently, a greater understanding of their at-sea habitat usage is a conservation priority. We used GPS tracking data from four UK Puffin colonies to construct species distribution models and examine colony- and individual-level variation in habitat usage in response to a suite of environmental covariates (chlorophyll-a concentration, sea surface temperature (SST), water depth, seabed slope, current velocity, and SST front gradient). The most consistent colony-level response was a negative association between habitat usage and chlorophyll-a concentration (observed at 3 out of 4 colonies). Responses to other environmental covariates were less consistent across colonies. Among individual variation in foraging range per trip was low, but we observed individual variation in habitat usage in response to almost all environmental covariates examined. Within each colony, we also identified distinct clusters of space-use across different groups of individuals. Different Puffin colonies and individuals are not ecologically equivalent. Therefore, perturbations to the marine environment are likely to have disproportionate effects on certain colonies and/or individuals. Incorporating colony- and individual-level variation will thus be essential for marine conservation efforts. [ABSTRACT FROM AUTHOR]

Plantain (Musa paradisiaca) has several bioactive components responsible for its pharmacological effects. The present study investigated the comparative antioxidative potential of different plantain part extracts: plantain whole fruit extract (PWFE), plantain pulp extract (PPPE), and plantain peel extract (PPLE) on FeSO₄-induced oxidative stress in isolated rat testes. Oxidative imbalance was induced in the rat testes ex vivo by incubating testis homogenate with 0.1 mM ferrous sulphate (FeSO4) in the presence or absence of plantain extracts at different concentrations (30, 60, 120, and 240 µg/mL) for 30 min at 37 °C. FeSO4 significantly reduced the levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), while elevating the level of oxidative stress markers like malondialdehyde (MDA). Furthermore, FeSO4 raised the levels of acetylcholine esterase (AChE) and nitric oxide (NO). Moreover, FeSO4 significantly elevated the levels of triglycerides, total cholesterol, low-density lipoprotein (LDL), and very low-density lipoprotein (vLDL), but reduced the level of high-density lipoprotein (HDL). However, PWFE, PPPE, and PPLE improved FeSO4-induced oxidative stress and lipid profiling. In particular, the extracts reduced the cellular concentrations of MDA, NO, AChE, cholesterol, triglycerides, LDL, and vLDL but elevated the levels of GSH, SOD, CAT, and HDL. The results demonstrate the capacity of the different parts of plantain to attenuate FeSO4-induced oxidative injury in rat testes ex vivo. [ABSTRACT FROM AUTHOR]

Introduction: Volatile organic compounds (VOCs) can arise from underlying metabolism and are detectable in exhaled breath, therefore offer a promising route to non-invasive diagnostics. Robust, precise, and repeatable breath measurement platforms able to identify VOCs in breath distinguishable from background contaminants are needed for the confident discovery of breath-based biomarkers. Objectives: To build a reliable breath collection and analysis method that can produce a comprehensive list of known VOCs in the breath of a heterogeneous human population. Methods: The analysis cohort consisted of 90 pairs of breath and background samples collected from a heterogenous population. Owlstone Medical's Breath Biopsy® OMNI® platform, consisting of sample collection, TD-GC-MS analysis and feature extraction was utilized. VOCs were determined to be "on-breath" if they met at least one of three pre-defined metrics compared to paired background samples. On-breath VOCs were identified via comparison against purified chemical standards, using retention indexing and high-resolution accurate mass spectral matching. Results: 1471 VOCs were present in > 80% of samples (breath and background), and 585 were on-breath by at least one metric. Of these, 148 have been identified covering a broad range of chemical classes. Conclusions: A robust breath collection and relative-quantitative analysis method has been developed, producing a list of 148 on-breath VOCs, identified using purified chemical standards in a heterogenous population. Providing confirmed VOC identities that are genuinely breath-borne will facilitate future biomarker discovery and subsequent biomarker validation in clinical studies. Additionally, this list of VOCs can be used to facilitate cross-study data comparisons for improved standardization. [ABSTRACT FROM AUTHOR]

The deposition of the amyloid-β (Aβ) peptide into amyloid fibrils is a hallmark of Alzheimer’s disease. Recently, it has been reported that some proteins can aggregate and form amyloids through an intermediate pathway involving a liquid-like condensed phase. These observations prompted us to investigate the phase space of Aβ. We thus explored the ability of Aβ to undergo liquid–liquid phase separation, and the subsequent liquid-to-solid transition that takes place within the resulting condensates. Through the use of microfluidic approaches, we observed that the 40-residue form of Αβ (Αβ40) can undergo liquid–liquid phase separation, and that accessing a liquid-like intermediate state enables Αβ40 to self-assemble and aggregate into amyloid fibrils through this pathway. These results prompt further studies to investigate the possible role of Αβ liquid–liquid phase separation and its subsequent aggregation in the context of Alzheimer’s disease and more generally on neurodegenerative processes. [ABSTRACT FROM AUTHOR]

Resting-state functional magnetic resonance imaging evolves through a repertoire of functional connectivity patterns which might reflect ongoing cognition, as well as the contents of conscious awareness. We investigated whether the dynamic exploration of these states can provide robust and generalizable markers for the state of consciousness in human participants, across loss of consciousness induced by general anaesthesia or slow wave sleep. By clustering transient states of functional connectivity, we demonstrated that brain activity during unconsciousness is dominated by a recurrent pattern primarily mediated by structural connectivity and with a reduced capacity to transition to other patterns. Our results provide evidence supporting the pronounced differences between conscious and unconscious brain states in terms of whole-brain dynamics; in particular, the maintenance of rich brain dynamics measured by entropy is a critical aspect of conscious awareness. Collectively, our results may have significant implications for our understanding of consciousness and the neural basis of human awareness, as well as for the discovery of robust signatures of consciousness that are generalizable among different brain conditions. Dynamical analysis of resting-state fMRI networks reveals a consistent increase in structure-function correlation and entropy decrease upon both general anesthesia-induced and deep sleep-induced loss of consciousness in humans. [ABSTRACT FROM AUTHOR]

The biological aspects of infancy within late Upper Palaeolithic populations and the role of southern refugia at the end of the Last Glacial Maximum are not yet fully understood. This study presents a multidisciplinary, high temporal resolution investigation of an Upper Palaeolithic infant from Grotta delle Mura (Apulia, southern Italy) combining palaeogenomics, dental palaeohistology, spatially-resolved geochemical analyses, direct radiocarbon dating, and traditional anthropological studies. The skeletal remains of the infant – Le Mura 1 – were directly dated to 17,320-16,910 cal BP. The results portray a biological history of the infant's development, early life, health and death (estimated at ~72 weeks). They identify, several phenotypic traits and a potential congenital disease in the infant, the mother's low mobility during gestation, and a high level of endogamy. Furthermore, the genomic data indicates an early spread of the Villabruna-like components along the Italian peninsula, confirming a population turnover around the time of the Last Glacial Maximum, and highlighting a general reduction in genetic variability from northern to southern Italy. Overall, Le Mura 1 contributes to our better understanding of the early stages of life and the genetic puzzle in the Italian peninsula at the end of the Last Glacial Maximum. Here, the authors present paleogenomics, dental histology, geochemistry, radiocarbon dating, and bioarchaeological analysis of an Upper Palaeolithic infant from Grotta delle Mura (southern Italy). These data depict the health and development of the individual and point to regional population turnover at the time. [ABSTRACT FROM AUTHOR]

Robotic surgery has expanded internationally at pace. There are multiple local robotic training pathways but there is inconsistency in standardisation of core common components for curricula internationally. A framework is required to define key objectives that can be implemented across robotic training ecosystems. This Delphi consensus aimed to provide recommendations for core considerations in robotic training design across diverse training environments internationally. A literature search was performed and an international steering committee (AG, KL, JW, HM, TC) proposed key components for contemporary robotic training design and a modified Delphi approach was used to gather stakeholder opinion. The outcomes were then discussed at a face-to-face international expert consensus at the IMRA educational session at the Society of Robotic Surgery (SRS) meeting and final voting was conducted on outstanding items. Stakeholders included robotic surgeons, proctors, trainees and robotic surgical training providers. There was consensus achieved in 139 statements organised into 15 themes. There was 100% agreement that standardised themes in robotic curricula may improve patient safety. Key take-home messages include—training curricula should be multiplatform, non-technical skills are an important component of a robotic curriculum as well as console and bedside skills, clinically relevant performance metrics should be used for assessment where available, the reliance on cadaveric and live animal models should be reduced as high-fidelity synthetic models emerge, and stepwise component training is useful for advanced procedural training. These consensus recommendations are intended to guide design of fit for purpose contemporary robotic surgical curricula. Integration of these components into robotic training pathways internationally is recommended. [ABSTRACT FROM AUTHOR]

Background: In post-mortem (PM) fetal and neonatal imaging, relevant clinical information is crucial for accurate interpretation and diagnosis; however, it is usually incomplete. Objective: To propose a standardized template for PM fetal and neonatal imaging referrals to enhance communication between referring clinicians and reporting radiologists. Materials and methods: A modified Delphi approach was conducted amongst members of the European Society of Paediatric Radiology (ESPR) PM Task Force and other recommended PM imaging specialists worldwide to determine consensus on necessary information. These were based on three pre-existing referral templates already in use across a variety of centers. The study ran for 4 months (December 2023–April 2024). Results: Nineteen specialists from 17 centers worldwide formed our expert panel. The final agreed referral template information includes the patient's identification details (mother and fetus when available), fetal/neonatal information (gestational age, sex, type of demise (including type of termination of pregnancy (i.e., surgical or medical)), date and time of fetal demise (+ delivery) or neonatal death, singleton/multiple pregnancy, clinical information (obstetrical history, prenatal imaging findings, amniocentesis findings, physical external examination findings), provisional clinical diagnosis, and ordering physician's information. Conclusion: A comprehensive referral template has been created, representing expert consensus on the minimum data required for the conduct of quality PM fetal and neonatal imaging, with the goal of facilitating accuracy of image interpretation. [ABSTRACT FROM AUTHOR]

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity. [ABSTRACT FROM AUTHOR]

The use of monoclonal antibodies for the control of drug resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A. baumannii. After immunisation of the Kymouse platform mice with A. baumannii derived outer membrane vesicles (OMV) we identify 297 antibodies and analyse 26 of these for functional potential. These antibodies target lipooligosaccharide (OCL1), the Oxa-23 protein, and the KL49 capsular polysaccharide. We identify a single monoclonal antibody (mAb1416) recognising KL49 capsular polysaccharide to demonstrate prophylactic in vivo protection against a carbapenem resistant A. baumannii lineage associated with neonatal sepsis mortality in Asia. Our end-to-end approach identifies functional monoclonal antibodies with prophylactic potential against major lineages of drug resistant bacteria accounting for phylogenetic diversity and clinical relevance without existing knowledge of a specific target antigen. Such an approach might be scaled for a additional clinically important bacterial pathogens in the post-antimicrobial era. In this work, the authors describe immunisation of human antibody immune repertoire transgenic mice as a surrogate to define protective human antibody reactivity to clinically diverse, antibiotic resistant Acinetobacter baumannii. [ABSTRACT FROM AUTHOR]

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3–KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3–KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling. The multidomain scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) can bind GTP-bound Ras and Rap small GTPases. Here the authors show that, by binding active KRAS, SHANK3 maintains oncogenic KRAS/MAPK/ERK signaling at an optimal level while its depletion in KRAS-mutant cancer cell lines results in ERK signalling overdose and impaired cell proliferation. [ABSTRACT FROM AUTHOR]

Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0–37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70–150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control. [ABSTRACT FROM AUTHOR]

Intratumoral injections have the potential for enhanced cancer treatment efficacy while reducing costs and systemic exposure. However, intratumoral drug injections can result in substantial off-target leakage and are invisible under standard imaging modalities like ultrasound (US) and x-ray. A thermosensitive poloxamer-based gel for drug delivery was developed that is visible using x-ray imaging (computed tomography (CT), cone beam CT, fluoroscopy), as well as using US by means of integrating perfluorobutane-filled microbubbles (MBs). MBs content was optimized using tissue mimicking phantoms and ex vivo bovine livers. Gel formulations less than 1% MBs provided gel depositions that were clearly identifiable on US and distinguishable from tissue background and with minimal acoustic artifacts. The cross-sectional areas of gel depositions obtained with US and CT imaging were similar in studies using ex vivo bovine liver and postmortem in situ swine liver. The gel formulation enhanced multimodal image-guided navigation, enabling fusion of ultrasound and x-ray/CT imaging, which may enhance targeting, definition of spatial delivery, and overlap of tumor and gel. Although speculative, such a paradigm for intratumoral drug delivery might streamline clinical workflows, reduce radiation exposure by reliance on US, and boost the precision and accuracy of drug delivery targeting during procedures. Imageable gels may also provide enhanced temporal and spatial control of intratumoral conformal drug delivery. [ABSTRACT FROM AUTHOR]

Effective ecosystem-based management of bottom-contacting fisheries requires understanding of how disturbances from fishing affect seafloor fauna over a wide range of spatial and temporal scales. Spatial predictions of abundance for 67 taxa were developed, using an extensive dataset of faunal abundances collected using a towed camera system and spatially explicit predictor variables including bottom-trawl fishing effort, using a Joint Species Distribution Model (JSDM). The model fit metrics varied by taxon: the mean tenfold cross-validated AUC score was 0.70 ± 0.1 (standard deviation) for presence–absence and an R2 of 0.11 ± 0.1 (standard deviation) for abundance models. Spatial predictions of probability of occurrence and abundance (individuals per km2) varied by taxon, but there were key areas of overlap, with highest predicted taxon richness in areas of the continental shelf break and slope. The resulting joint predictions represent significant advances on previous predictions because they are of abundance, allow the exploration of co-occurrence patterns and provide credible estimates of taxon richness (including for rare species that are often not included in more commonly used single-species distribution modelling). Habitat-forming taxa considered to be Vulnerable Marine Ecosystem (VME) indicators (those taxa that are physically or functionally fragile to anthropogenic impacts) were identified in the dataset. Spatial estimates of likely VME distribution (as well as associated estimates of uncertainty) were predicted for the study area. Identifying areas most likely to represent a VME (rather than simply VME indicator taxa) provides much needed quantitative estimates of vulnerable habitats, and facilitates an evidence-based approach to managing potential impacts of bottom-trawling. [ABSTRACT FROM AUTHOR]

This article starts from two observations about archival description. First, creating finding aids requires significant judgment and interpretation, and is therefore inevitably influenced by the positionalities—the perspectives, personal histories, and social identities—of the archivists. Second, finding aids occasionally call for revision, sometimes to fit a new data standard or reflect an evolving collection, but also to correct errors, reduce bias, and remove harmful language. In light of these observations, this article has two aims. First, it develops and presents a theoretical rationale for recording metadata about finding aids, including revision history and authorship, arguing for transparency about positionality as a response to recognizing the infeasibility of impartiality. Second, it presents the results of a survey of state archivists in the US, who were asked about their descriptive practices and their attitudes regarding disclosing their authorship of finding aids. Results of the survey reveal diverse practices, as well as some hesitation to embrace expressions of positionality in the context of description. The article closes with a discussion of options for conceptualizing metadata about finding aids and the professional role of archivists, concluding with two general recommendations. [ABSTRACT FROM AUTHOR]

Objectives: Corner metaphyseal lesions (CMLs) are specific for child abuse but challenging to detect on radiographs. The accuracy of CT for CML detection is unknown. Our aim was to compare diagnostic accuracy for CML detection on post-mortem skeletal surveys (PMSS, plain radiography) versus post-mortem CT (PMCT). Methods: A 10-year retrospective review was performed at a children's hospital for patients having PMSS, PMCT and histopathological correlation (reference standard) for suspected CMLs. Twenty-four radiologists independently reported the presence or absence of CMLs in all cases in a blinded randomised cross-over design across two rounds. Logistic regression models were used to compare accuracy between modalities. Results: Twenty CMLs were reviewed for each of the 10 subjects (200 metaphyses in all). Among them, 20 CMLs were confirmed by bone histopathology. Sensitivity for these CMLs was significantly higher for PMSS (69.6%, 95% CI 61.7 to 76.7) than PMCT (60.5%, 95% CI 51.9 to 68.6). Using PMSS for detection of CMLs would yield one extra correct diagnosis for every 11.1 (95% CI 6.6 to 37.0) fractured bones. In contrast, specificity was higher on PMCT (92.7%, 95% CI 90.3 to 94.5) than PMSS (90.5%, 95% CI 87.6 to 92.8) with an absolute difference of 2.2% (95% CI 1.0 to 3.4, p < 0.001). More fractures were reported collectively by readers on PMSS (785) than on PMCT (640). Conclusion: PMSS remains preferable to PMCT for CML evaluation. Any investigation of suspected abuse or unexplained deaths should include radiographs of the limbs to exclude CMLs. Clinical relevance statement: In order to avoid missing evidence that could indicate child abuse as a contributory cause for death in children, radiographs of the limbs should be performed to exclude CMLs, even if a PMCT is being acquired. Key Points: • Corner metaphyseal lesions (CMLs) are indicative for abuse, but challenging to detect. Skeletal surveys (i.e. radiographs) are standard practice; however, accuracy of CT is unknown. • Sensitivity for CML detection on radiographs is significantly higher than CT. • Investigation of unexplained paediatric deaths should include radiographs to exclude CMLs even if CT is also being performed. [ABSTRACT FROM AUTHOR]

A study was conducted to investigate the temperature dependence of thermomechanical coupling in Inconel 718 (IN718). IN718 was selected as a model material due to deformation being predominantly accommodated by planar slip. Split-Hopkinson (or Kolsky) tension bar experiments were conducted at a nominal strain rate of 750 s - 1 at room temperature and 450 ∘ C, representing homologous temperatures ( T H = T / T melt ) of T H = 0.2 and T H = 0.5 , respectively. During deformation, specimen gauge sections were imaged with a high-speed infrared camera. Using one-dimensional wave analysis, the transient heat conduction equation, and temperature-dependent specific heat capacity values, the temperature rise as a function of plastic strain was used to calculate plastic work, thermal work, and the plastic work to heat conversion efficiency, commonly known as the Taylor–Quinney coefficient (TQC). As expected, a significant reduction in plastic work was observed during testing at elevated temperatures. The temperature rise due to plastic deformation was observed to be lower at room temperature compared to elevated temperature experiments. It is reported here for the first time that the TQC is a temperature-sensitive quantity. At T H = 0.5 , a nearly complete conversion of plastic work to heat was observed (TQC ≈ 1.0 ). Under ambient conditions of T H = 0.2 , a much lower efficiency TQC ≈ 0.4 was observed. [ABSTRACT FROM AUTHOR]

Abstract We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS‐CoV‐2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large‐scale community effort to build an open access, interoperable and computable repository of COVID‐19 molecular mechanisms. The COVID‐19 Disease Map (C19DMap) is a graphical, interactive representation of disease‐relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph‐based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS‐CoV‐2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID‐19 or similar pandemics in the long‐term perspective.

We pursue a uniform quantization of all twists of 4-dimensional N = 4 supersymmetric Yang–Mills theory, using the BV formalism, and we explore consequences for factorization algebras of observables. Our central result is the construction of a one-loop exact quantization on R 4 for all such twists and for every point in a moduli of vacua. When an action of the group SO (4) can be defined—for instance, for Kapustin and Witten's family of twists—the associated framing anomaly vanishes. It follows that the local observables in such theories can be canonically described by a family of framed E 4 algebras; this structure allows one to take the factorization homology of observables on any oriented 4-manifold. In this way, each Kapustin–Witten theory yields a fully extended, oriented 4-dimensional topological field theory à la Lurie and Scheimbauer. [ABSTRACT FROM AUTHOR]

Background: High-intensity actions have gained increasing significance in contemporary football. Among these actions, the spotlight shines on the enhancement of change of direction (COD) speed. Several training methods have been employed to elevate this skill in football players, with plyometric training (PT) being one of the viable approaches. The objective of this review is to identify the diverse variables crucial for implementing an optimal PT regimen aimed at enhancing COD speed in football players. Design: A systematic examination was conducted involving previously published original experimental studies featuring control groups, the utilization of PT as a training modality, and the evaluation of one or multiple instances of COD in football players. Method: A systematic search was conducted on March 13, 2023, encompassing the MEDLINE, SPORTDiscus, and Web of Science databases. The quest was aimed at locating studies that incorporated control groups, adopted PT as a training methodology, and measured one or multiple COD scenarios, with studies being published in either English or Spanish. Results: A total of 34 studies were encompassed in this systematic review. Remarkably, with the exception of one, all the studies exhibited enhancements in COD performance through qualitative assessments when employing PT. It appears that PT, when used in isolation, is not outperformed by PT combined with another training method in the context of enhancing COD speed, provided that the overall training load remains unchanged. Conclusion: To improve COD speed in football players, a PT program spanning 6–9 weeks, featuring two weekly sessions with a 48 to 72-h rest interval between sessions, is advisable. The program should include 1–6 exercises that incorporate both unilateral and bilateral executions across various planes, performed at maximum intensity. Additionally, rest intervals between sets should range from 60 to 90 s, and the number of contacts should be increased by 60–200. [ABSTRACT FROM AUTHOR]

The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001–2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S. biomedical researchers. Four MMPCLive Centers located at universities around the country perform complex and often unique procedures in vivo on a fee for service basis, typically on mice shipped from the client or directly from a repository or vendor. Current areas of expertise include energy balance and body composition, insulin action and secretion, whole body carbohydrate and lipid metabolism, cardiovascular and renal function, food intake and behavior, microbiome and xenometabolism, and metabolic pathway kinetics. Additionally, an opportunity arose to reduce barriers to access and expand the diversity of the biomedical research workforce by establishing the VIBRANT Program. Directed at researchers historically underrepresented in the biomedical sciences, VIBRANT-eligible investigators have access to testing services, travel and career development awards, expert advice and experimental design consultation, and short internships to learn test technologies. Data derived from experiments run by the Centers belongs to the researchers submitting mice for testing which can be made publicly available and accessible from the MMPCLive database following publication. In addition to services, MMPCLive staff provide expertise and advice to researchers, develop and refine test protocols, engage in outreach activities, publish scientific and technical papers, and conduct educational workshops and training sessions to aid researchers in unraveling the heterogeneity of diabetes and obesity. [ABSTRACT FROM AUTHOR]

Several studies have been published describing development of cutaneous malignancy after vismodegib therapy; no systematic review has been conducted to interpret these data. Our objective was to systemically review reported cases of same-site or different-site cutaneous malignancy after smoothened inhibitor (SMOi) therapy for primary basal cell carcinoma (BCC). PubMed, CINAHL, and Scopus were systematically searched January 1, 2012 – March 28, 2024. Inclusion criteria: primary BCC, SMOi therapy, and biopsy-proven secondary malignancy. Exclusion criteria: non-human subjects. Bias was assessed using Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Twenty-three cases describing same-site secondary malignancy were included. Average patient age was 67.2 years, mean treatment time 8.4 months, and average latency period to secondary malignancy development of 10.2 months. Five cases describing different-site secondary cutaneous malignancies were included. Mean patient age was 80.4 years, mean treatment time 2.9 months, and mean latency period 4.5 months. Twenty-seven cases were associated with vismodegib, while one case described vismodegib then sonidegib therapy. Pathologies included squamous cell carcinoma, BCC, basosquamous carcinoma, and malignant melanoma. The mechanism(s) by which same-site and different-site secondary malignancy occur are not known; mechanisms may differ depending on location type and secondary tumor type. We discuss multiple mechanistic hypotheses including pharmacologic selective pressure leading to hedgehog pathway mutant cells and activation of pro-growth signaling, and potential protective effect of hedgehog inhibition from melanoma given reports of rapid growth after SMOi discontinuation. This study is limited by the small number of reported cases. Additional research is needed to investigate these hypotheses. [ABSTRACT FROM AUTHOR]

Emotion studies have commonly reported impaired emotional processing in individuals with heightened anhedonic depressive symptoms, as typically measured by collecting single subjective ratings for a given emotional cue. However, the interindividual variation in moment-to-moment emotional reactivity, and associated time-varying brain networks recruitment as emotions are unfolding, remains unclear. In this study, we filled this gap by using the unique temporal characteristics of music to investigate behavioural and brain network dynamics as a function of anhedonic depressive symptoms severity. Thirty-one neurotypical participants aged 18–30 years completed anhedonic depression questionnaires and then continuously rated happy, neutral and sad pieces of music whilst undergoing MRI scanning. Using a unique combination of dynamic approaches to behavioural (i.e., emotion dynamics) and fMRI (i.e., leading eigenvector dynamics analysis; LEiDA) data analysis, we found that participants higher in anhedonic depressive symptoms exhibited increased recruitment of attentional networks and blunted emotional response to both happy and sad musical excerpts. Anhedonic depression mediated the relationship between attentional networks recruitment and emotional blunting, and the elevated recruitment of attentional networks during emotional pieces of music carried over into subsequent neutral music. Future studies are needed to investigate whether these findings could be generalised to a clinical population (i.e., major depressive disorder). [ABSTRACT FROM AUTHOR]

Cancer is a condition that affects the psychological integrity of patients, due to the stigma that persists in relation to the disease. The aim of this study was to evaluate the presence of symptoms of anxiety, depression and the quality of life in patients undergoing total thyroidectomy for differentiated thyroid cancer and compare with patients undergoing total thyroidectomy for benign nodular disease. Cross-sectional study, conducted at the Irmandade da Santa Casa de Misericórdia in São Paulo, Brazil. A total of 64 patients submitted to total thyroidectomy were evaluated. Group A was composed of 29 patients with differentiated thyroid cancer and Group B was composed of 32 patients with benign nodular disease. Sociodemographic data were collected, Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were used to identify symptoms of anxiety and depression. Quality of life was analyzed using Quality of Life Instrument (WHOQOL – BREF). The mean age was 49 ± 12 years, and 82.8% were female. Patients with differentiated thyroid cancer had higher levels of anxiety (BAI: 17.3 ± 11.4 vs. 10.3 ± 8.6) and depression (BDI: 12.6 ± 6.4 vs. 5.9 ± 7,2) compared to patients with benign nodular disease. The WHOQOL-BREF showed lower scores in the differentiated thyroid cancer group in relation to the benign nodular disease group for all domains evaluated: physical, psychological, social relationships, environment, self-assessment of quality of life, and general quality of life. Patients undergoing total thyroidectomy for differentiated thyroid cancer have more symptoms of anxiety and depression and a poorer quality of life when compared with patients undergoing total thyroidectomy due to benign nodular disease. [ABSTRACT FROM AUTHOR]

Background: Tuberous sclerosis complex (TSC) is a rare approximate 1:6000 birth incidence, a genetic disease with a wide variability of physical and neuropsychiatric symptoms. Patients require lifelong care from multiple healthcare specialities, for which International and United Kingdom (UK) TSC consensus recommendations exist. Personalised care delivered by a centralised coordinated team of TSC experts is recommended. There is no such service for the estimated 600 TSC patients in the Republic of Ireland (ROI) and there is a paucity of information regarding the healthcare of this group. Purpose: Evaluate the baseline care of patients with TSC attending epilepsy services in the Republic of Ireland (ROI) against UK TSC consensus recommendations. Methods: Patients with a diagnosis of TSC attending 12 adult and paediatric epilepsy centres in the ROI were identified. Clinical audits measured the baseline care of a subset of these patients against UK, TSC clinical recommendations. Data was anonymised and analysed at Trinity College Dublin. Results: One hundred thirty-five TSC patients attending twelve epilepsy centres were identified. Adults (n = 67) paediatric (n = 68). The care of 83 patients was audited (n = 63 ≥ 18 years) and (n = 20 < 18 years). Many baseline tests were completed, however, they required intra or interhospital referral. Care appears fragmented and there was no evidence of formal disease surveillance plans. Conclusions: The number of TSC patients attending epilepsy services is lower than expected (n = 135). Specialist services and treatments for TSC are available through informal referral pathways. Although UK, TSC consensus baseline recommendations are roughly adhered to, care is fragmented. Increased coordination of care could benefit disease management. [ABSTRACT FROM AUTHOR]

Many analyses in particle and nuclear physics use simulations to infer fundamental, effective, or phenomenological parameters of the underlying physics models. When the inference is performed with unfolded cross sections, the observables are designed using physics intuition and heuristics. We propose to design targeted observables with machine learning. Unfolded, differential cross sections in a neural network output contain the most information about parameters of interest and can be well-measured by construction. The networks are trained using a custom loss function that rewards outputs that are sensitive to the parameter(s) of interest while simultaneously penalizing outputs that are different between particle-level and detector-level (to minimize detector distortions). We demonstrate this idea in simulation using two physics models for inclusive measurements in deep inelastic scattering. We find that the new approach is more sensitive than classical observables at distinguishing the two models and also has a reduced unfolding uncertainty due to the reduced detector distortions. [ABSTRACT FROM AUTHOR]

Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, phosphorylation is important for β-arrestin recruitment to the receptor, and ligands of different efficacies induce distinct phosphorylation barcodes. The C-tail 370TREHPSTANT379 motif harbours Ser/Thr residues important for these regulatory functions. 375Ser is the primary phosphorylation site of a ligand-dependent, hierarchical, and sequential process, whereby flanking 370Thr, 376Thr and 379Thr get subsequently and rapidly phosphorylated. Here we used GRK KO cells, phosphosite specific antibodies and site-directed mutagenesis to evaluate the contribution of the different GRK subfamilies to ligand-induced phosphorylation barcodes and β-arrestin2 recruitment. We show that both GRK2/3 and GRK5/6 subfamilies promote phosphorylation of 370Thr and 375Ser. Importantly, only GRK2/3 induce phosphorylation of 376Thr and 379Thr, and we identify these residues as key sites to promote robust β-arrestin recruitment to the MOR. These data provide insight into the mechanisms of MOR regulation and suggest that the cellular complement of GRK subfamilies plays an important role in determining the tissue responses of opioid agonists. CRISPR/Cas9 knock-out of GRKs combined with mutagenesis and phospho-specific antibodies reveal the sites of the mu-opioid receptor that underlie the differences in regulation of this receptor by morphine and fentanyl. [ABSTRACT FROM AUTHOR]

Key message: Integrating disease screening data and genomic data for host and pathogen populations into prediction models provides breeders and pathologists with a unified framework to develop disease resistance. Developing disease resistance in crops typically consists of exposing breeding populations to a virulent strain of the pathogen that is causing disease. While including a diverse set of pathogens in the experiments would be desirable for developing broad and durable disease resistance, it is logistically complex and uncommon, and limits our capacity to implement dual (host-by-pathogen)-genome prediction models. Data from an alternative disease screening system that challenges a diverse sweet corn population with a diverse set of pathogen isolates are provided to demonstrate the changes in genetic parameter estimates that result from using genomic data to provide connectivity across sparsely tested experimental treatments. An inflation in genetic variance estimates was observed when among isolate relatedness estimates were included in prediction models, which was moderated when host-by-pathogen interaction effects were incorporated into models. The complete model that included genomic similarity matrices for host, pathogen, and interaction effects indicated that the proportion of phenotypic variation in lesion size that is attributable to host, pathogen, and interaction effects was similar. Estimates of the stability of lesion size predictions for host varieties inoculated with different isolates and the stability of isolates used to inoculate different hosts were also similar. In this pathosystem, genetic parameter estimates indicate that host, pathogen, and host-by-pathogen interaction predictions may be used to identify crop varieties that are resistant to specific virulence mechanisms and to guide the deployment of these sources of resistance into pathogen populations where they will be more effective. [ABSTRACT FROM AUTHOR]