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Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer’s disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P= 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P= 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P= 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds’ potencies were evaluated in calcium mobilization and radioligand binding assays, and structure–activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3′-methoxy-[1,1′-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, Ki8.91 nM) and its 3′-trifluoromethyl analog (54, PSB-24040, Ki83.2 nM). Receptor–ligand docking studies revealed that the compounds’ binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. ‘Ultimate genotypes’, in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology.

The costs of treating bladder cancer in the USA are high, expected to have exceeded $6.5 billion in the year 2021. The average cost for newly diagnosed patients ranges from $19,521 for the earliest stage of disease to $169,533 for metastatic disease. Average costs per patient increase upon disease recurrence and more effective initial treatments to delay disease recurrence or progression may reduce the costs associated with bladder cancer.

The movement of large amounts of nutrients by migrating animals has ecological benefits for recipient food webs1,2that may be offset by co-transported contaminants3,4. Salmon spawning migrations are archetypal of this process, carrying marine-derived materials to inland ecosystems where they stimulate local productivity but also enhance contaminant exposure5–7. Pacific salmon abundance and biomass are higher now than in the last century, reflecting substantial shifts in community structure8that probably altered nutrient versus contaminant delivery. Here we combined nutrient and contaminant concentrations with 40 years of annual Pacific salmon returns to quantify how changes in community structure influenced marine to freshwater inputs to western North America. Salmon transported tonnes of nutrients and kilograms of contaminants to freshwaters annually. Higher salmon returns (1976–2015) increased salmon-derived nutrient and contaminant inputs by 30% and 20%, respectively. These increases were dominated by pink salmon, which are short-lived, feed lower in marine food webs than other salmon species, and had the highest nutrient-to-contaminant ratios. As a result, the delivery of nutrients increased at a greater rate than the delivery of contaminants, and salmon inputs became more ecologically beneficial over time. Even still, contaminant loadings may represent exposure concerns for some salmon predators. The Pacific salmon example demonstrates how long-term environmental changes interact with nutrient and contaminant movement across large spatial scales and provides a model for exploring similar patterns with other migratory species9.

Dihydroazepino[1,2-a]indole diones are tricyclic N-acyl-2-alkylidene-3-oxindole enones that readily engage in tertiary phosphine-catalyzed intermolecular coupling reactions with acceptor-substituted alkenes. In these reactions, the tricyclic α-substituted enones undergo an α-alkylation with concomitant formation of a quaternary stereocenter, as well as the installation of a new double bond within the seven-membered azepane ring. The organocatalytic reaction constitutes a special case of the crossed intermolecular Rauhut–Currier reaction as the presence of the α-substituent in the enones prohibits the formation of an α,β-unsaturated product, but instead, skipped β,γ-unsaturated enones are obtained. With allene carboxylates as alternative coupling partners, the crossed Rauhut–Currier-type reaction competes with a regioselective allene to enone [3 + 2]-cycloaddition, and the product selectivity can be controlled by the choice of the phosphine organocatalyst.

ABSTRACTIntroductionT-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein – coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM.Areas coveredThis review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response.Expert opinionTo further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response. An important open question is also to what extent response to BsAbs can be improved when these agents are used in earlier lines of therapy. In addition, more evidence is needed on rational de-intensification strategies of BsAb dosing upon achieving a sufficient response, and if (temporary) treatment cessation is possible in patients who have achieved a deep remission (e.g. complete response or minimal residual disease-negative status).

Selective catalytic oxidation (SCO) of humins is a promising strategy to valorize undesired side streams of biomass conversion processes. Keggin-type polyoxometalates are efficient catalysts for the SCO of humins giving platform chemicals like formic acid, acetic acid or their respective esters up to combined yields of 51 %. Moreover, one of the main challenges for establishing continuous processes is the efficient catalyst recycling and product separation. Herein, we combined an optimization study for the process parameters in SCO with an integrated product separation carried out by using nanofiltration membranes. For this purpose, an enhanced reaction system consisting of 5 vol% methanol addition for CO2suppression in combination with 1.5 mmol pTSA as solubility promotor was applied using H5[PV2Mo10O40] (HPA-2) as a catalyst achieving a maximum humin conversion of 90 % resulting in 57 % carboxylic ester selectivity. In subsequent studies, an appropriate XN 45 nanofiltration membrane was identified allowing for >99 % catalyst and >90 % additive retention efficiently separating the acidic reaction products in the permeate. Furthermore, long-time stability of the membrane and thus of the separation process could be confirmed up to 168 h time on stream. Based on these results, the developed process represents an important milestone in the valorization of humins combined with efficient separation of the molecular polyoxometalate catalyst and could therefore be the basis for future developments.

Gram-negative bacteria develop and exhibit resistance to antibiotics, owing to their highly asymmetric outer membrane maintained by a group of six proteins comprising the Mla (maintenance of lipid asymmetry) pathway. Here, we investigate the lipid binding preferences of one Mla protein, MlaC, which transports lipids through the periplasm. We used ultraviolet photodissociation (UVPD) to identify and characterize modifications of lipids endogenously bound to MlaC expressed in three different bacteria strains. UVPD was also used to localize lipid binding to MlaC residues 130–140, consistent with the crystal structure reported for lipid-bound MlaC. The impact of removing the bound lipid from MlaC on its structure was monitored based on collision cross section measurements, revealing that the protein unfolded prior to release of the lipid. The lipid selectivity of MlaC was evaluated based on titrimetric experiments, indicating that MlaC-bound lipids in various classes (sphingolipids, glycerophospholipids, and fatty acids) as long as they possessed no more than two acyl chains.

Obstacle resolving micro-scale atmospheric models (ORMs) are important to assess atmospheric processes within urban areas. However, the data generated from such models are not standardised yet and existing data standards do not fit properly to those data. Standardised model data can help to prepare FAIR data publications, which foster the process of data reuse, sharing, comparison and distribution. Therefore, an online survey was distributed among ORM users and developers in the urban meteorology and urban climate community. The survey should help to assess, which models are currently in use and to collect suggestions and requirements from the participants on how a data standard should look like. The aim of the survey was not to test the knowledge of the participants about the model they use but rather to get an overview of how they understand, use and work with ORMs. Based on 14 finished survey entries, it shows that ORMs provide and handle their data differently. The participants are aware of the need for standardisation, preferring netCDF as data format and suggesting extending existing standards to the needs of ORM data.

Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e., l-idose or l-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity.

AbstractCrosscutting concepts (CCs) are designed to help students make sense of phenomena across multiple scientific disciplines. We describe an instructional approach that scaffolds students’ use of CCs to help students make sense of and ask productive questions about an anchoring phenomenon. We share analysis of students’ use of language of the seven CCs in their initial questions added to the Driving Question Board in three different high school storyline units. Our goals were to see how students use different CCs and how we can support student use of targeted CCs in instructional units. We found that students used some CCs more often than others when developing questions. These questions were productive as they were well aligned to the core science ideas that are developed in subsequent lessons, supporting the finding that CCs are a low-threshold sensemaking tool for all students. We describe how the analysis informed revisions of each of the units to strengthen supports for students’ use of particular CCs in their sensemaking of phenomena. We also discuss instructional approaches that can be incorporated within lessons and across units to help develop and deepen students’ three-dimensional science understandings.

This study determined a cost-effective larval diet for rearing Calliphora dubiaMacquart for use as a potential managed pollinator in Australia. This fly has potential as a pollination species to support honey bees (Apis mellifera). Larvae of C. dubiawere reared mostly in meat meals with varying amounts of either whole egg powder, whole eggs (+ shell), bran flakes, skimmed milk powder, brewer’s yeast, or poultry oil. This was done from an economic and production perspective to support commercial rearing. Several laboratory-based studies determined the growth and output from various ingredient combinations. Larvae fed 90% meat meal and 10% whole egg powder developed rapidly through to pupation with a high pupation rate, adult size, and percent adult emergence. Given the high cost and difficulty in sourcing whole egg powder, media comprising mostly meat meals with the addition of bran flakes and whole eggs also supported rapid larval development, pupation rate, and adult emergence. The ideal amount of media/larvae was 0.5 g/larvae to support high pupation rates and adult emergence. Adult eclosion occurred over 4–5 days, even when larvae were laid and fed within 1 h on ample media. Commercial mass rearing would then require daily cohorts of larvae to ensure peak adult fly emergence over 1–2 days for release into a crop. Mass-rearing C. dubiashould use meat meal as the base ingredient with bran flakes and whole eggs added and fed at 0.5 g of media/larvae. Based on the current media ingredient costs, rearing 1-m adult C. dubiawould cost just over $500 (US$342).

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This editorial takes stock of the importance of public procurement for international business (IB) and the research questions that remain. We argue that, apart from its traditional role of providing public services to citizens, public procurement acts as a demand-led policy instrument in which governments attempt to influence market outcomes by acting as large discretionary buyers and using their purchasing power and administrative processes to obtain policy objectives. We compare various financial and non-financial goals that governments aim to attain with public procurement and how they try to shape IB to achieve these goals. We also develop a framework to analyze how contracting firms and their global value chains adapt their IB strategies to optimize their chance of winning public procurement contracts.

The wetting of (mixed) self-assembled monolayers (SAMs) is characterized as a function of surface charge. Using a combination of molecular dynamics simulations and contact angle measurements, we unravel the arrangement of dipoles and hydrogen bonds at the interface. Our basis simulation model features alkyl functionalization of an aluminum oxide surface via n-alkyl-phosphonic acid [C18H37–PO(OH)2] molecules, which represents a commonly used hydrophobic SAM surface readily accessible to contact angle measurements. We then probed the effect of charging the alkyl-terminated SAMs to unravel the interplay of local hydrophobicity and the overall dipole arrangement within the droplets. Strikingly, we find that moderate positive charging retains the hydrophobic character and potentially makes the SAMs even more hydrophobic than their uncharged counterpart. We attribute this phenomenon to the hindering of dangling hydrogen atoms at the water-alkyl contact, as a consequence of dipole rearrangements. While our simulation models predict a contact angle increase by 10° as an upper estimate for boosting hydrophobicity, experimental analyses of mixed SAMs using imidazole/alkyl-terminated species showed roughly constant wetting behavior for moderately positive charging.

AbstractBackgroundCurrently available risk scores fail to accurately predict morbidity and mortality in patients with severe symptomatic aortic stenosis who undergo transcatheter aortic valve implantation (TAVI). In this context, biomarkers like matrix metalloproteinase-2 (MMP-2) and Galectin-3 (Gal-3) may provide additional prognostic information.MethodsPatients with severe aortic stenosis undergoing consecutive, elective, transfemoral TAVI were included. Baseline demographic data, functional status, echocardiographic findings, clinical outcomes and biomarker levels were collected and analysed.ResultsThe study cohort consisted of 89 patients (age 80.4 ± 5.1 years, EuroScore II 7.1 ± 5.8%). During a median follow-up period of 526 d, 28 patients (31.4%) died. Among those who died, median baseline MMP-2 (alive: 221.6 [170.4; 263] pg/mL vs.deceased: 272.1 [225; 308.8] pg/mL, p < 0.001) and Gal-3 levels (alive: 19.1 [13.5; 24.6] pg/mL vs. deceased: 25 [17.6; 29.5] pg/mL, p = 0.006) were higher than in survivors. In ROC analysis, MMP-2 reached an acceptable level of discrimination to predict mortality (AUC 0.733, 95% CI [0.62; 0.83], p < 0.001), but the predictive value of Gal-3 was poor (AUC 0.677, 95% CI [0.56; 0.79], p = 0.002). Kaplan–Meier and Cox regression analyses showed that patients with MMP-2 and Gal-3 concentrations above the median at baseline had significantly impaired long-term survival (p = 0.004 and p = 0.02, respectively).ConclusionsIn patients with severe aortic stenosis undergoing transfemoral TAVI, MMP-2 and to a lesser extent Gal-3, seem to have additive value in optimizing risk prediction and streamlining decision-making.

ABSTRACTThis editorial examines diversity from the perspective of the marginalised diverse. Space is created here for diverse voices, encouraging submissions from emerging economies and from those who have otherwise felt the marginalisation of dominating norms. [Tanima, F., and S. George. 2024. When the personal is political: Sharing our lived experiences as women of colour in academia. Social Environmental and Accountability Journal44, no. 2] draw from early personal journals to provide relatable reflections, through a rich narrative of career experiences, both as accounting academics and as women of colour. [Lima, J.P., C. Miranda, and S. Casa Nova. 2024. Is there no sin down south of the equator? Brazilian auditors’ perception of the gendered and racialized dynamics in audit firms. Social Environmental and Accountability Journal44, no. 2] then discuss the oppressive, gendered and racialised dynamics found within the Brazilian context. [Pereira, D., M.J. d’Angelo, and B. Cola. 2024. Queer performance of gay and cis men accountants from the perspective of tokenism. Social Environmental and Accountability Journal44, no. 2] mobilise queer insights and notions of symbolic tokenism, to analyse interview-based experiences of cisgendered gay men working in the accounting profession in Brazil, providing insights on how impeding social structures can persist, despite increasing legal protections. [Anderson-Gough, F., C. Edgley, K. Robson, and N. Sharma. 2024. Cultural circularities that limit diversity: Emancipating voices. Social Environmental and Accountability Journal44, no. 2] complete the special issue, with a thoughtful and personal conceptualisation of a range of ‘loop’ types which limit the effectiveness of organisational attention to equity, diversity and inclusion. This special issue points to the nuanced challenges faced, whether social, cultural or legal, from one geographic context to another. We end by calling for further exploration of lived experiences and diverse voices by the marginalised and managed diverse.

Fewer than half of America’s college students complete their bachelor’s degrees. To many, cost seems to be the crucial barrier. Sociologists of education have long argued, though, that inequalities start before costs matter. Entrenched “sort and sieve” processes apportion outcomes to family background. The whole system of grading, testing, and selecting some students while rejecting others makes a degree much more likely for students from higher status families—and that system was in place long before states limited appropriations and tuition skyrocketed. Analyzing longitudinal data from three cohorts of high school students, we find only small changes in the college graduation rate as of 1988, 1998, and 2010. Second, baseline socioeconomic and racial disparities in college completion were just as high in 1988 as in 2010. Third, mediation analysis shows that half of the socioeconomic disparities work through pre-college factors such as grades and curriculum choices. The other half reflect higher graduation rates at selective colleges. Fourth, the only notable change concerned community colleges; the potential disadvantage of starting at one declined after the 1980s. Our analysis affirms sociologists’ focus on persistent aspects of academic sorting, not recent changes, as the root of inequality of opportunity in American higher education.