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Metalated intact and deprotonated histidyl glycine and glycyl histidine dipeptides were investigated in the gas phase by using infrared multiple photon dissociation (IRMPD) spectroscopy with light from a free-electron laser (FEL). The dipeptides M2+(GlyHis), M2+(HisGly), [M(GlyHis-H)]+, and [M(HisGly-H)]+, where M = Zn and Cd, were probed to elucidate how the His position along the peptide chain and ligand charge state might influence the structures observed in the gas phase. Simulated annealing calculations were performed to determine energetically low-lying conformers and isomers of these structures. Quantum chemical calculations were used to optimize the structures at the B3LYP level of theory using the 6-311+G(d,p) and def2-TZVP basis sets for zinc and cadmium complexes, respectively. IRMPD and calculated linear absorption spectra were compared to evaluate which structures are present. Relative energies of the various species were evaluated using single-point energy calculations for low-lying structures at the B3LYP, B3LYP-GD3BJ, ωB97XD, and MP2(full) levels using the 6-311+G(2d,2p) and def2-TZVPP basis sets. For all species, structures for both metals mirror each other, and those that reproduce the experimental spectrum were determined to be iminol structures for the intact ligands or iminol-like structures for the deprotonated ligands. Additionally, when the spectra of the deprotonated dipeptides are compared to the intact dipeptides, the change in the spectra is correlated to the group that is deprotonated.

Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.

The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.

Confinement of clathrate hydrate enables an energy efficient, cyclic and carbon neutral storage concept in which CO2, generated by E-methane conversion, replaces E-methane by direct exchange.

Freezing of Gait (FoG) is a common symptom of Parkinson’s disease (PD), manifesting as a brief, episodic absence, or marked reduction in walking, despite a patient’s intention to move. Clinical assessment of FoG events from manual observations by experts is both time-consuming and highly subjective. Therefore, machine learning-based FoG identification methods would be desirable. In this article, we address this task as a fine-grained human action recognition problem based on vision inputs. A novel deep learning architecture, namely, higher order polynomial transformer (HP-Transformer), is proposed to incorporate pose and appearance feature sequences to formulate fine-grained FoG patterns. In particular, a higher order self-attention mechanism is proposed based on higher order polynomials. To this end, linear, bilinear, and trilinear transformers are formulated in pursuit of discriminative fine-grained representations. These representations are treated as multiple streams and further fused by a cross-order fusion strategy for FoG detection. Comprehensive experiments on a large in-house dataset collected during clinical assessments demonstrate the effectiveness of the proposed method, and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.92 is achieved for detecting FoG.

Aim:To compare the microbial communities inside hemodialysis catheters from symptomatic and asymptomatic patients to determine their differences.Materials & methods:Catheters (n = 41) were removed from patients in the Saskatchewan Health Authority over an 18-month period. The catheter section inside the body was flushed and the contents were evaluated using culture-dependent and culture-independent analysis.Results:All catheters were colonized by bacteria, with considerable overlap between groups based on microbial communities and the individual species detected. More Gram-negative species were detected by sequencing, whereas predominantly Gram-positive strains were cultured. Antibiotic resistance and biofilm formation was widespread and not correlated with either catheter group.Conclusion:Common pathogens were detected in each set of catheters, therefore predicting infections based on the microbiology is difficult.

Purpose:To evaluate the visual outcomes and complications with a polytetrafluoroethylene (Gore-Tex)-fixated intraocular lens (IOL) (Akreos AO60, Bausch + Lomb). Methods:Eyes with inadequate capsule support for in-the-bag IOL implantation had pars plana vitrectomy (PPV) and IOL placement at a single center. The main outcome measures were the postoperative visual acuity (VA) and complication rates. Results:During the study, 783 surgeries were performed. The mean visual acuity gain was 28.5 Early Treatment Diabetic Retinopathy Study letters (P< .01), with a mean time to best VA of 3.05 months. Statistical hypotony (intraocular pressure <6.5 mm Hg) was present in 214 cases (27.3%), and clinical features of hypotony were present in 46 cases. Five percent of the complications were directly related to the IOL. There were 3 cases of IOL opacification, 2 with silicone oil endotamponade and 1 with perfluoropropane endotamponade. Conclusions:PPV with Akreos IOL implantation was an effective technique for secondary IOL placement. Complications directly related to the IOL were uncommon.

Les commotions cérébrales dans le sport représentent un défi majeur avec des implications importantes pour la santé des athlètes. Cet article présente des cas cliniques variés de commotions cérébrales dans le sport, offrant un aperçu des situations auxquelles les professionnels de santé sont confrontés. Le premier cas présente Alice, une joueuse de football de 18 ans, qui souffre de symptômes postcommotionnels après une collision. Les outils SCAT6® sont utilisés pour confirmer sa commotion et les recommandations incluent le repos relatif et une reprise progressive des activités cognitives et sportives. Le deuxième cas décrit Arthur, un demi-centre de handball de 20 ans, qui, après un choc violent, veut retourner au jeu malgré des symptômes initiaux importants. Il est évalué avec SCAT6® et ne peut pas reprendre le jeu immédiatement. Le troisième cas concerne Léo, un jeune joueur de hockey de 10 ans, dont les symptômes persistent une semaine après l’accident. Le SCOAT6 est utilisé pour son évaluation, et ses activités scolaires et sportives sont adaptées pour éviter toute exacerbation. Enfin, le quatrième cas présente Louise, une skieuse alpine de 24 ans, ayant subi plusieurs commotions cérébrales avec des répercussions croissantes sur sa santé et sa carrière sportive. Elle est évaluée avec SCOAT6 et doit suspendre son sport jusqu’à la disparition des symptômes. Ces cas soulèvent des questions critiques pour les professionnels de la santé : quels outils utiliser pour évaluer les commotions, quelles recommandations donner pour le retour au sport et à l’école, et comment gérer les facteurs aggravants ? En se basant sur ces situations réelles, l’article vise à enrichir les connaissances et les pratiques des médecins et des professionnels de santé, en mettant en lumière l’importance d’une évaluation rigoureuse et des recommandations adaptées.

La fiche synthèse pour l’utilisation des outils SCAT6® et SCOAT6 aide les cliniciens à comprendre et utiliser ces outils recommandés par la 6econférence de consensus sur les commotions cérébrales de 2022. Les commotions cérébrales, blessures courantes mais graves, nécessitent une prise en charge rapide. Le SCAT6® (Sport Concussion Assessment Tool) et le SCOAT6 (Sport Concussion Office Assessment Tool) fournissent des directives claires pour l’évaluation immédiate sur le terrain, le suivi à court terme et la gestion à long terme des commotions cérébrales. Cette fiche décrit l’utilisation de ces outils pour différentes situations cliniques, de l’évaluation initiale à la prise en charge post-commotionnelle, incluant des suggestions thérapeutiques adaptées.

An analytical theory for the interaction potential between surfaces (e.g., colloids) in polyelectrolyte solutions is derived. A superposition of a Debye–Hückel interaction potential and a damped oscillatory interaction potential, commonly employed to fit measured colloidal interactions, follows naturally from our theory. Using appropriate expressions for the structure factor of the bulk polyelectrolyte solution in the dilute, semidilute and concentrated regimes explicit expressions for the wavelength and decay length of the oscillatory part of the interaction potential were derived. Quantitative agreement between experimental measurements and our theory is found in the dilute and semidilute concentration regimes. In the concentrated regime, the theory predicts very weak oscillations and a large attractive region due to the electrostatically induced depletion interactions, in agreement with simulations.

Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure.

To determine the pathophysiologic and prognostic meaning of patient self-reported sodium intake in heart failure (HF) with preserved ejection fraction (HFpEF).

Rescoring of peptide–spectrum matches (PSMs) has emerged as a standard procedure for the analysis of tandem mass spectrometry data. This emphasizes the need for software maintenance and continuous improvement for such algorithms. We introduce MS2Rescore 3.0, a versatile, modular, and user-friendly platform designed to increase peptide identifications. Researchers can install MS2Rescore across various platforms with minimal effort and benefit from a graphical user interface, a modular Python API, and extensive documentation. To showcase this new version, we connected MS2Rescore 3.0 with MS Amanda 3.0, a new release of the well-established search engine, addressing previous limitations on automatic rescoring. Among new features, MS Amanda now contains additional output columns that can be used for rescoring. The full potential of rescoring is best revealed when applied on challenging data sets. We therefore evaluated the performance of these two tools on publicly available single-cell data sets, where the number of PSMs was substantially increased, thereby demonstrating that MS2Rescore offers a powerful solution to boost peptide identifications. MS2Rescore’s modular design and user-friendly interface make data-driven rescoring easily accessible, even for inexperienced users. We therefore expect the MS2Rescore to be a valuable tool for the wider proteomics community. MS2Rescore is available at https://github.com/compomics/ms2rescore.

Data-independent acquisition (DIA) has become a well-established method for MS-based proteomics. However, the list of options to analyze this type of data is quite extensive, and the use of spectral libraries has become an important factor in DIA data analysis. More specifically the use of in silico predicted libraries is gaining more interest. By working with a differential spike-in of human standard proteins (UPS2) in a constant yeast tryptic digest background, we evaluated the sensitivity, precision, and accuracy of the use of in silico predicted libraries in data DIA data analysis workflows compared to more established workflows. Three commonly used DIA software tools, DIA-NN, EncyclopeDIA, and Spectronaut, were each tested in spectral library mode and spectral library-free mode. In spectral library mode, we used independent spectral library prediction tools PROSIT and MS2PIP together with DeepLC, next to classical data-dependent acquisition (DDA)-based spectral libraries. In total, we benchmarked 12 computational workflows for DIA. Our comparison showed that DIA-NN reached the highest sensitivity while maintaining a good compromise on the reproducibility and accuracy levels in either library-free mode or using in silico predicted libraries pointing to a general benefit in using in silico predicted libraries.

Ni-rich layered oxides LiNi1–x–yMnxCoyO2(NMC811, x= 0.1 and y= 0.1) are considered promising cathode materials in lithium-ion batteries (LiBs) due to their high energy density. However, those suffer a severe capacity loss upon cycling at high delithiated states. The loss of performance over time can be retarded by Zr doping. Herein, a small amount of Zr is added to NMC811 material via two alternative pathways: during the formation of the transition metal (TM) hydroxide precursor at the co-precipitation step (0.1%-Zr-cp) and during the lithiation at the solid-state synthesis step (0.1%-Zr-ss). In this work, the crystallographic Zr uptake in both 0.1%-Zr-ss and 0.1%-Zr-cp is determined and quantified through synchrotron X-ray diffraction and X-ray absorption spectroscopy. We prove that the inclusion of Zr in the TM site for 0.1%-Zr-cp leads to an improvement of both specific capacity (156 vs 149 mAh/g) and capacity retention (85 vs 82%) upon 100 cycles compared to 0.1%-Zr-ss where the Zr does not diffuse into the active material and forms only an extra phase separated from the NMC811 particles.

The article highlights the dynamic and engaging atmosphere created by Opera Revue, a group revitalizing the Toronto music scene with their unique opera performances in casual settings. Topics include the casual and welcoming ambiance of Opera Revue's performances, the group's founding and key members, and the diverse audience they attract.

Nanopore field-effect transistor (NP-FET) devices hold great promise as sensitive single-molecule sensors, which provide CMOS-based on-chip readout and are also highly amenable to parallelization. A plethora of applications will therefore benefit from NP-FET technology, such as large-scale molecular analysis (e.g., proteomics). Due to its potential for parallelization, the NP-FET looks particularly well-suited for the high-throughput readout of DNA-based barcodes. However, to date, no study exists that unravels the bit-rate capabilities of NP-FET devices. In this paper, we design DNA-based barcodes by labeling a piece of double-stranded DNA with dumbbell-like DNA structures. We explore the impact of both the size of the dumbbells and their spacing on achievable bit-rates. The conformational fluctuations of this DNA-origami, as observed by molecular dynamics (MD) simulation, are accounted for when selecting label sizes. An experimentally informed 3D continuum nanofluidic–nanoelectronic device model subsequently predicts both the ionic current and FET signals. We present a barcode design for a conceptually generic NP-FET, with a 14 nm diameter pore, operating in conditions corresponding to experiments. By adjusting the spacing between the labels to half the length of the pore, we show that a bit-rate of 78 kbit·s–1is achievable. This lies well beyond the state-of-the-art of ≈40 kbit·s–1, with significant headroom for further optimizations. We also highlight the advantages of NP-FET readout based on the larger signal size and sinusoidal signal shape.

ABSTRACTSearch engines match user queries with webpages. Search efficiency, increases when data-driven network effects attract more users and generate economies of scale and scope in data aggregation. Network effects enhance user welfare but also trigger antitrust concerns because they may “tip” the market towards a single dominant search engine – Google Search. The EU Digital Markets Act imposes an obligation on very large gatekeepers search engines to share their user data with smaller search engines to facilitate market entry and competition. The available empirical literature on search engine efficiency shows that asymmetric data sharing, from larger to smaller search engines, may increase competition but reduce user welfare because it fragments the user data pool that is crucial for efficiency, in particular for rare queries. Tension between competition and user welfare can be overcome by symmetric and mutual data sharing between all search engines, irrespective of market share.

Citrusfruits are among the most economically important crops in the world. In the global market, the Citrus peel is often considered a byproduct but substitutes an important phenotypic characteristic of the fruit and a valuable source of essential oils, flavonoids, carotenoids, and phenolic acids with variable concentrations. The Mediterranean basin is a particularly dense area of autochthonous genotypes of Citrusthat are known for being a source of healthy foods, which can be repertoires of valuable genes for molecular breeding with the focus on plant resistance and quality improvement. The scope of this study was to characterize and compare the main phenotypic parameters (i.e., peel thickness, fruit volume, and area) and levels of bioactive compounds in the peel of fruits from the local germplasm of Citrusin Greece, to assess their chemodiversity regarding their polyphenolic, volatile, and carotenoid profiles. A targeted liquid chromatographic approach revealed hesperidin, tangeretin, narirutin, eriocitrin, and quercetin glycosides as the major polyphenolic compounds identified in orange, lemon, and mandarin peels. The content of tangeretin and narirutin followed the tendency mandarin > orange > lemon. Eriocitrin was a predominant metabolite of lemon peel, following its identification in lower amounts in mandarin and at least in the orange peel. For these citrus-specific metabolites, high intra- but also interspecies chemodiversity was monitored. Significant diversity was found in the essential oil content, which varied between 1.2 and 3% in orange, 0.2 and 1.4% in mandarin, and 0.9 and 1.9% in lemon peel. Limonene was the predominant compound in all Citrusspecies peel essential oils, ranging between 88 and 93% among the orange, 64 and 93% in mandarin, and 55 and 63% in lemon cultivars. Carotenoid analysis revealed different compositions among the Citrusspecies and accessions studied, with β-cryptoxanthin being the most predominant metabolite. This large-scale metabolic investigation will enhance the knowledge of Citruspeel secondary metabolite chemodiversity supported by the ample availability of Citrusgenetic resources to further expand their exploitation in future breeding programs and potential applications in the global functional food and pharmaceutical industries.

During World War II, Canadian pilot Robert Leslie Spence and Australian gunner John Wood were shot down over Africa and had to trek over 500 kilometers through the African desert to find safety. They endured extreme heat and limited supplies before reaching British-occupied territory and being rescued by a British advance armoured division. Their story was published in a comic book called "Men against the Desert," which depicted them as heroes and was well-received by readers. Spence and Wood survived the war and lived fulfilling lives. [Extracted from the article]

L’harmonisation des connaissances sur les commotions cérébrales dans le milieu sportif représente un défi majeur en Europe et au Canada francophones. L’étude conduite par le Réseau Francophone Olympique de la Recherche en Médecine du sport (ReFORM) visait à dresser un état des lieux des connaissances actuelles des acteurs de terrain (professionnels de santé, entraîneurs et athlètes) concernant la prévention et la gestion des commotions cérébrales dans le sport. Pour ce faire, un questionnaire en ligne a été complété par 2073 participants dans les pays francophones composant le réseau ReFORM (Belgique, Canada, France, Luxembourg et Suisse). Les résultats ont montré que les niveaux de connaissance et d’accès à l’éducation sur les commotions cérébrales variaient considérablement et significativement selon la profession et la région géographique. En effet, les professionnels de santé ont affiché un niveau de connaissance généralement supérieur comparé aux entraîneurs et aux athlètes. De plus, les participants du Canada francophone ont démontré un meilleur niveau de connaissance et d’accès aux ressources éducatives par rapport à leurs homologues européens. Cette étude met en évidence la nécessité d’améliorer la diffusion des connaissances sur les commotions cérébrales, en particulier chez les entraîneurs et les athlètes en Europe et de développer des programmes éducatifs spécifiques pour chaque groupe cible afin d’améliorer la santé et la sécurité des athlètes.

Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy.

The article offers information on Stephanie Martin, who was appointed Artistic Director and Conductor of Brott Music Festival and its training programs. Topics include Martin's impressive credentials and experience, including her education in conducting, past roles as Assistant and Associate Conductor for the Vancouver Symphony, and her extensive work with orchestras and chamber orchestras in Canada, the United States, and Europe.

Purpose:Most infants born preterm will experience some difficulty with sucking and feeding. As clinicians in the neonatal intensive care unit (NICU), it is important to understand the available technologies so that they may be implemented, when appropriate and accessible, to support these infants in their sucking and feeding performance. The purpose of this review is to highlight devices that are available to assist clinicians in the management of pediatric dysphagia in the NICU. We will review the literature surrounding the use of devices in the management of pediatric dysphagia. This is followed by a clinical perspective from a NICU speech-language pathologist (SLP) who shares important considerations, recommendations, and limitations of device use.Conclusions:By reviewing device-facilitated therapies for the management of pediatric dysphagia and discussing their implementation and effectiveness, we hope that SLPs will gain an understanding of the available technologies and insight into their use in the NICU environment. While the research highlighted shows many benefits of the use of device-facilitated therapies in the NICU, this is an emerging area of the field that is continually evolving and more research is needed to establish the pathway to individualized, developmentally supportive, device-facilitated intervention.

Assessment of functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) is essential for risk stratification, and it traditionally relied on cardiopulmonary exercise testing (CPET)–derived peak oxygen consumption (peak Vo2).

Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. Here, we used a combination of systematic glycosylation reactions, the characterization of potential reactive intermediates, and in-depth computational studies to study the disparate behavior of glycosylation systems involving benzylidene glucosyl and mannosyl donors. While these systems have been studied extensively, no satisfactory explanations are available for the differences observed between the 3-O-benzyl/benzoyl mannose and glucose donor systems. The potential energy surfaces of the different reaction pathways available for these donors provide an explanation for the contrasting behavior of seemingly very similar systems. Evidence has been provided for the intermediacy of benzylidene mannosyl 1,3-dioxanium ions, while the formation of the analogous 1,3-glucosyl dioxanium ions is thwarted by a prohibitively strong flagpole interaction of the C-2-O-benzyl group with the C-5 proton in moving toward the transition state, in which the glucose ring adopts a B2,5-conformation. This study provides an explanation for the intermediacy of 1,3-dioxanium ions in the mannosyl system and an answer to why these do not form from analogous glucosyl donors.

ABSTRACTIntroductionThe objective and significance of the topic is to draw attention toward regulatory aspects (and pharmacopoeias) for bioequivalence investigation, and perception for generic pharmaceuticals, especially their stereoselective bioequivalence evaluation for understanding the performance of the racemic generic products available in the market.Areas coveredThe areas covered include bioequivalence studies (and related USP and FDA requirements) on certain generic APIs for comparison, examples of concern related to inspection of pharmaceuticals for export/import. Literature methodology includes search through USP monographs, MDPI.com, msn.com, WHO Drug Information, certain specific web links, PubMed Central®, PubMed®, NLM’s advanced biomedical information services, and several pdf published in relevant journals in the field for related authentic information.Expert opinionThe USP, the USFDA, and the units alike internationally should enforce pharmaceutical companies to perform stereoselective investigations on generic APIs to show that their PK/PD parameters are (nearly) equal to the standards set by such units for allowing marketing of that API. This should be provided to professionals in the areas of patient care and every country should enforce such regulations at the time of export and import of generics.

The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

Toxicological assessments of newly developed agrochemical agents consider chemical modifications and their metabolic and biotransformation products. To carry out an in silico hazard assessment, understanding the type of chemical modification and its location on the original compound can greatly enhance the reliability of the evaluation. Here, we present and apply a method based on liquid chromatography–mass spectrometry (LC–MS) enhanced with infrared ion spectroscopy (IRIS) to better delineate the molecular structures of transformation products before in silico toxicology evaluation. IRIS facilitates the recording of IR spectra directly in the mass spectrometer for features selected by retention time and mass-to-charge ratio. By utilizing quantum-chemically predicted IR spectra for candidate molecular structures, one can either derive the actual structure or significantly reduce the number of (isomeric) candidate structures. This approach can assist in making informed decisions. We apply this method to a plant growth stimulant, digeraniol sinapoyl malate (DGSM), that is currently under development. Incubation of the compound in Caco-2 and HepaRG cell lines in multiwell plates and analysis by LC–MS reveals oxidation, glucuronidation, and sulfonation metabolic products, whose structures were elucidated by IRIS and used as input for an in silico toxicology assessment. The toxicity of isomeric metabolites predicted by in silico tools was also assessed, which revealed that assigning the right metabolite structure is an important step in the overall toxicity assessment of the agrochemical. We believe this identification approach can be advantageous when specific isomers are significantly more hazardous than others and can help better understand metabolic pathways.

ABSTRACTDespite the major historical significance of the Great Depression, little scholarly research exists that analyzes the state of newspaper advertising during the 1930s, particularly in the hard-hit Dust Bowl states. Using Taylor’s six-segment message strategy wheel, this research examined display advertising during one of the most difficult years in the most difficult places: 1934 in the Dust Bowl region of Nebraska, Colorado, Kansas, Oklahoma, New Mexico, and Texas. Results show that essential services, such as banks, utilities, and transportation, primarily used the informational/rational strategy to provide reassurance and empathy to consumers. However, nonessential industries, such as cosmetics, expensive home goods, and tobacco, often used the transformational/sensory approach to encourage high-quality experiences through spending. This historical analysis offers a unique opportunity for contemporary advertisers to understand how past advertising strategies during a crisis influence the present.

Telomere length (TL) is a biomarker linked to age-related diseases based on its sensitivity to oxidative DNA damage and inflammation. Methylmercury (MeHg) is a common pollutant in fish. It may induce oxidative stress leading to shorter TL. However, previous research showed contradictory results and dose-concentration dependencies and non-linear relationships have been suggested. This study was carried out in the INMA multi-center birth cohort prospective study comprising mother–child pairs belonging to four different Spanish cohorts from 2004. We set out to assess the association between prenatal and 4-year-old children's exposure to MeHg with TL at the ages of 4 and 7–9 years (n= 1083). Sociodemographic and lifestyle covariates, as well as fish consumption and estimated polyunsaturated fatty acid content, were also considered in the analyses. A mixed regression model and interaction models based on sex and fish consumption were performed. Sensitivity analyses to assess confounding effects were also built by adding to the main model other pollutants present in fish, such as other metals, polychlorinated biphenyls, and dichlorodiphenyldichloroethylene, as well as single nucleotide polymorphisms in the TERT and CLPTM1Lgenes. Longer TL was associated with higher paternal age and female sex in children. MeHg concentrations were related to higher maternal age, being primiparous, working during pregnancy, higher education, and higher fish consumption. No significant associations between prenatal or postnatal MeHg concentrations and TL were found. Sensitivity analyses showed no MeHg modification effect on TL. Further research is needed to elucidate the TL modifications found by previous studies associated with MeHg and fish consumption.

Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3variant carrier compared to controls. TSHZ3was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3variants in a 5′ region were more frequent in CAKUT patients than in gnomAD samples (p< 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.

Eukaryotic innate immune systems use pattern recognition receptors to sense infection by detecting pathogen-associated molecular patterns, which then triggers an immune response. Bacteria have similarly evolved immunity proteins that sense certain components of their viral predators, known as bacteriophages1–6. Although different immunity proteins can recognize different phage-encoded triggers, individual bacterial immunity proteins have been found to sense only a single trigger during infection, suggesting a one-to-one relationship between bacterial pattern recognition receptors and their ligands7–11. Here we demonstrate that the antiphage defence protein CapRelSJ46in Escherichia colican directly bind and sense two completely unrelated and structurally different proteins using the same sensory domain, with overlapping but distinct interfaces. Our results highlight the notable versatility of an immune sensory domain, which may be a common property of antiphage defence systems that enables them to keep pace with their rapidly evolving viral predators. We found that Bas11 phages harbour both trigger proteins that are sensed by CapRelSJ46during infection, and we demonstrate that such phages can fully evade CapRelSJ46defence only when both triggers are mutated. Our work shows how a bacterial immune system that senses more than one trigger can help prevent phages from easily escaping detection, and it may allow the detection of a broader range of phages. More generally, our findings illustrate unexpected multifactorial sensing by bacterial defence systems and complex coevolutionary relationships between them and their phage-encoded triggers.

In the realm of automated vehicles (AVs), the focus is predominantly on the potential of sub-symbolic deep-learning-based artificial intelligence (AI) systems. Our study questions the suitability of this data-driven approach for AVs, particularly in embodying societal values in their behaviour. Through a systematic examination of sub-symbolic and symbolic AI, we identify key issues for AVs, including adaptability, safety, reliability, trust, fairness, transparency, and control. Deep learning systems’ lack of adaptability and inherent complexities pose significant safety concerns and hinder meaningful human control. This limitation prevents humans from effectively updating AI decision-making processes to better reflect ethical values. Furthermore, deep learning systems are prone to biases and unfairness, leading to incidents that are difficult to explain and rectify. In contrast, symbolic, model-based approaches offer a structured framework for encoding ethical goals and principles within AV systems, thus enabling meaningful human control. However, they also face challenges, such as inefficiencies in handling large amounts of unstructured data for low-level tasks and maintaining explicit knowledge bases. Therefore, we advocate for hybrid AI, combining symbolic and sub-symbolic models with symbolic goal functions. We propose Augmented Utilitarianism (AU) as an ethical framework for developing these goal functions, aiming to minimise harm by integrating principles from consequentialism, deontology, and virtue ethics, while incorporating the perspective of the experiencer. Our methodology for eliciting moral attributes to construct an explicit ethical goal function engages collective societal values through iterative refinement, contributing to the development of safer, more reliable, and ethically aligned automated driving systems.

Inductive heating swing adsorption (IHSA) using hybrid adsorbents incorporating a porous material and ferrite nanoparticles holds promise to be a performant, electrified alternative for conventional gas separation. Successful implementation of hybrid adsorbents in IHSA depends on achieving a maximal specific absorption rate (SAR) in the conditions and at the frequency of the induction setup. This paper outlines and demonstrates successful strategies for optimization of the particle composition, tailoring the coercivity and susceptibility of the ferrite particles to optimal performance in a given alternating magnetic field.

This pilot study assessed the acceptance and use of the e-Health instrument “the Personal Health Check” (PHC) among clients and professionals in primary care settings. By filling in the online PHC instrument, participants were provided insights into their health and lifestyle. When results revealed an increased health risk, participants were advised to undertake additional lab tests measuring blood pressure and haemaglobin levels. Based on the online questionnaire and optional lab tests, participants then received a report that included individually-tailored feedback from the e-Health application about personal health risks and suggestions for health interventions. The PHC was implemented in 2016 in four Dutch municipalities that determined which neighbourhood(s) the PHC targeted and how participants were invited. The Unified Theory of Acceptance and Use of Technology was used as a theoretical framework to address our research questions. Methods used to assess acceptance were: PHC instrument data, data from additional questionnaires completed by PHC participants, focus groups with PHC participants and professionals in primary care, and telephone interviews with non-responders to the invitation to participate in the online PHC. Of the 21,735 invited, 12% participated. Our results showed that participants and professionals in this pilot were predominantly positive about the PHC. Participants reported that they made an effort to apply the PHC lifestyle advice they received. Almost all had the knowledge and resources needed to use the PHC online instrument. Invitations from general practitioners almost doubled participation relative to invitations from the sponsoring municipalities. The overall low response rate, however, suggests that the PHC is unsuitable as a foundation on which to develop local public health policy.

Fuelled by the benefits of The Internet of Things (IoT), Artificial Intelligence (AI), big data and cloud computing, South Korean consumers demand more affordable, nutritious and healthier food options. With Samsung as the market leader in IoT, a mixed methodology, qualitative action-based approach was used to identify how Samsung may expand IoT services into South Korea's industrial, agricultural sectors for efficiency and sustainability. Nonghyup's representative of the South Korean Farmers' Agricultural Association was surveyed, resulting in four IoT-based smart grid initiatives. It was found that despite Samsung's strong brand recognition and high product utilisation and IoT's ability to boost South Korean farming output efficiency, IoT use in South Korean agriculture is largely unknown. By merging AI and technological devices, Samsung may aid farmers to adapt its technology and build sustainability and consumers alike to enable individuals to grow food in their homes. The utilisation of IoT in farming can have broad applicability in a wide variety of international agricultural markets, providing a tool to combat food security issues.

IntroductionMid-portion Achilles tendinopathy (mid-AT) is currently the preferred term for persistent Achilles tendon pain, defined as located 2–7 cm proximal to the calcaneus, and with loss of function related to mechanical loading. Histologically, mid-AT is considered to represent a degenerative condition. Therefore, monitoring of tendon structure additional to pain and function may be warranted, to prevent progression of degeneration or even tendon rupture. The aim of this study was to determine the association between pain and function, relative to the Achilles tendon structure, in soldiers treated with a conservative programme for mid-AT.MethodsA total of 40 soldiers (40 unilateral symptomatic tendons) were included in this study. Pain and function were evaluated with the Victorian Institute of Sports Assessment -Achilles (VISA-A) questionnaire. Tendon structure was quantified using ultrasound tissue characterisation (UTC). We quantified both the Achilles tendon mid-portion (2–7 cm) and the area of maximum degeneration (AoMD) within the tendon mid-portion. VISA-A and UTC measurements were taken at baseline and after 26 weeks of follow-up. Spearman’s rho was used to determine the correlation between VISA-A and UTC. Correlations were calculated for baseline, follow-up and change score values.ResultsNegligible correlations were found for all analyses, ranging from −0.173 to 0.166 between mid-portion tendon structure and VISA-A, and from −0.137 to 0.150 between AoMD and VISA-A. While VISA-A scores improved, on average, from 59.4 points at baseline to 93.5 points at follow-up, no detectable improvement in aligned fibrillar structure was observed in our population.ConclusionPain and function are poorly associated with Achilles tendon structure in soldiers treated with a conservative programme for mid-AT. Therefore, we advise clinicians to use great caution in communicating relationships between both clinical entities.Trial registration numberNL69527.028.19.

Purpose: The study aimed to evaluate temporary fillings using Biodentine™ in asymptomatic deep carious lesions after 12, 24, and 36 months in school children from the remote village of Kerung, Nepal. Methods: From November 2018 to November 2019, 91 temporary fillings were placed using Biodentine™ (a hydraulic calcium silicate cement) in permanent molars with deep carious lesions of schoolchildren in the remote district of Kerung, Nepal. These restorations were performed after selective caries removal in a non-dental setting with hand instruments and cotton roll isolation, as electric motors and saliva ejection systems were unavailable. In total, 78 single-surface and 13 multi-surface fillings were placed. Clinical and radiographic follow-up periods encompassed 12, 21, and 33 months, respectively. Results: After 12 months, all single-surface fillings (100%) survived, whilst all multi-surface fillings were partially or entirely lost. The survival rate of single-surface restorations after 21 and 33 months was 67.6% and 50%, respectively. Radiographically, no pathology was observed. Conclusion: This study showed that Biodentine could be used in deep carious lesions as a temporary filling in single-surface lesions for at least up to 1 year and in a substantial number of cases for up to 21 and 33 months.

Chronic calorie restriction (CR) improves cardiovascular function and several other physiological markers of healthspan. However, CR is impractical in non-obese older humans due to potential loss of lean mass and bone density, poor adherence, and risk of malnutrition. Time-restricted feeding (TRF), which limits the daily feeding period without requiring a reduction in calorie intake, may be a promising alternative healthspan—extending strategy for midlife and older adults; however, there is limited evidence for its feasibility and efficacy in humans. We conducted a randomized, controlled pilot study to assess the safety, tolerability, and overall feasibility of short-term TRF (eating <8 h day−1for 6 weeks) without weight loss in healthy non-obese midlife and older adults, while gaining initial insight into potential efficacy for improving cardiovascular function and other indicators of healthspan. TRF was safe and well-tolerated, associated with excellent adherence and reduced hunger, and did not influence lean mass, bone density, or nutrient intake. Cardiovascular function was not enhanced by short-term TRF in this healthy cohort, but functional (endurance) capacity and glucose tolerance were modestly improved. These results provide a foundation for conducting larger clinical studies of TRF in midlife and older adults, including trials with a longer treatment duration.

The most recent European regulation, the Euro 6d emission standard, requires all gasoline direct injection (GDI) vehicles to use both a three-way catalyst (TWC) and a gasoline particle filter (GPF) as exhaust aftertreatment. These aftertreatment methods are aimed at reducing NOxand primary particle emissions. However, the formation of secondary organic aerosols (SOAs) from the volatile organic compound (VOC) emissions of a Euro 6d compliant GDI vehicle, factory equipped with a GPF is not yet investigated. Therefore, to explore the SOA formation and effects of the GPF, the exhaust of a Euro 6d compliant GDI vehicle was characterized at 4 different steady state speeds, idling (0 km h−1), 50, 80 and 100 km h−1. The exhaust was oxidised in a photochemical emission aging flow tube reactor (PEAR) by reactions with OH radicals equivalent of 2.2 days of atmospheric day time oxidation. It was found that the GPF completely removes primary particles larger than 10 nm, at all investigated vehicle speeds. However, significant SOA was formed after oxidation, with the highest SOA formation potential per kg fuel consumed at 50 km h−1. The main SOA precursors were determined to be toluene, xylene and trimethyl-benzene which were found to account for at least 50% of SOA formed at all driving speeds. Furthermore, high emissions of ammonia (NH3) could be observed in the exhaust under all driving conditions which resulted in the subsequent formation of ammonium nitrate (NH4NO3) after aging. The formation of NH4NO3additionally facilitated the co-condensation of organic gas phase products after OH oxidation enhancing SOA mass even further.

Oxidation flow reactors (OFRs) have been increasingly used to conduct research on secondary aerosol formation potential and composition in laboratory and field studies by exposing aerosols to high levels of oxidants in short time periods. In order to assess the atmospheric relevance of the triggered chemical reactions, kinetic models have been developed to reveal the production of atmospheric oxidants and the fate of volatile organic compounds (VOCs). However, it is unknown how different OFR conditions generating the same OH exposure affect the chemical and physical properties of the secondary aerosol particle phase because the model is based on gas phase chemistry. Toluene as a well-investigated precursor of secondary organic aerosols (SOAs) was aged in the high-volume OFR “PEAR” at three different external OH reactivities (OHRext) and in an environmental chamber at the same OH exposure of (1.09 ± 0.09) × 1011s cm−3. These specific OFR conditions altered the majority of the investigated chemical and physical properties of the toluene-derived SOA (tol-SOA). However, OFR-aging at low OHRextassociated with atmospherically relevant conditions did not lead to physical and chemical SOA properties most similar to chamber-generated SOAs at the same low OHRext. Particularly, for the most detailed chemical analysis by electrospray (ESI) high-resolution Orbitrap mass spectrometry (HRMS), tol-SOA from the PEAR at high OHRext, deviating from atmospherically relevant conditions, and the chamber were most different to tol-SOA from the PEAR with low and medium OHRext. Our study challenges the concept of atmospherically relevant OFR aerosol aging and motivates further exploration of OFR conditions on secondary aerosol composition.

Game description languages have a variety of uses, including formal reasoning about the emergent consequences of a game's mechanics, implementation of artificial intelligence decision making where the game's rules make up the space of possible actions, automated game and level generation, and game prototyping for the sake of low-time-investment design and tinkering. However, in practice, a new game description language has been invented for almost every new use case, without providing formal underpinnings that follow generalizable principles and can be reasoned about separately from the specific software implementation of the language. Ceptre is a language that attempts to break this pattern, based on an old idea known as multiset rewriting. This article describes the language formally, through example, and in a tutorial style, then demonstrates its use for writing formal specifications of game mechanics so that they may be interactively explored, queried, and analyzed in a computational framework. Ceptre allows designers to step through executions, interact with the mechanics from the standpoint of a player, run random simulated playthroughs, collect and analyze data from said playthroughs, and formally verify mathematical properties of the mechanics, and it has been used in a number of research projects since its inception, for applications such as procedural narrative generation, formal game modeling, and game AI.