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Exploring platinum (Pt)-solute nanoparticles (NPs) with multifaceted geometries, multifunctionality, and extended stability is key for several electrocatalytic applications. Here, we demonstrate that Pt-based alloy NPs modified with molybdenum (Mo) exhibit superior electrocatalytic properties compared with pure Pt NPs. Electrocatalytic testing of these Mo-modified Pt nanoalloys shows excellent catalytic performance in the hydrogen evolution reaction (HER), the oxygen reduction reaction (ORR), and the methanol oxidation reaction (MOR). We show that the catalytic functionalities in the ORR and the MOR achieved by the Mo-modified Pt nanoalloys are 15-25 times greater than the standard commercial Pt/C nanocatalyst. These nanoalloys also show enhanced resistance to poisoning by carbon monoxide (CO) adlayers and stability after accelerated durability tests (ADTs). We associate the origin of these exceptional electrocatalytic performances of the Pt-solute-Mo nanoalloys with their high degree of concavity, variations in vertex chemistry, and Pt enrichment along the corners and edges. Our findings offer a facile synthetic approach for the synthesis of Pt-solute nanoalloys as high-performance multifunctional electrocatalysts.

Galactose is a secondary fermentable sugar that requires specific regulatory and structural genes for its assimilation, which are under catabolite repression by glucose. When glucose is absent, the catabolic repression is attenuated, and the structural GAL genes are fully activated. In Saccharomyces cerevisiae, the GAL pathway is under selection in environments where galactose is present. However, it is unclear the adaptive strategies in response to long-term propagation in galactose as a sole carbon source in laboratory evolution experiments. Here, we performed a 4,000-generation evolution experiment using 48 diploid Saccharomyces cerevisiae populations to study adaptation in galactose. We show that fitness gains were greater in the galactose-evolved population than in identically evolved populations with glucose as a sole carbon source. Whole-genome sequencing of 96 evolved clones revealed recurrent de novo single nucleotide mutations in candidate targets of selection, copy number variations, and ploidy changes. We find that most mutations that improve fitness in galactose lie outside of the canonical GAL pathway. Reconstruction of specific evolved alleles in candidate target of selection, SEC23 and IRA1, showed a significant increase in fitness in galactose compared to glucose. In addition, most of our evolved populations (28/46; 61%) fixed aneuploidies on Chromosome VIII, suggesting a parallel adaptive amplification. Finally, we show greater loss of extrachromosomal elements in our glucose-evolved lineages compared with previous glucose evolution. Broadly, these data further our understanding of the evolutionary pressures that drive adaptation to less-preferred carbon sources.

Seasonal snowmelt from the Wasatch Mountains of northern Utah, USA is a primary control on water availability for the metropolitan Wasatch Front, surrounding agricultural valleys, and the Great Salt Lake (GSL). Prolonged drought, increased evaporation due to warming temperatures, and sustained agricultural and domestic water consumption have caused GSL water levels to reach record low stands in 2021 and 2022, resulting in increased exposure of dry lakebed sediment. When dust emitted from the GSL dry lakebed is deposited on the adjacent Wasatch snowpack, the snow is darkened, and snowmelt is accelerated. Regular observations of dust-on-snow (DOS) began in the Wasatch Mountains in 2009, and the 2022 season was notable for both having the most dust deposition events and the highest snowpack dust concentrations. To understand if record high DOS concentrations were linked to record low GSL levels, dust source regions for each dust event were identified through a backward trajectory model analysis combined with aerosol measurements and field observations. Backward trajectories indicated that the exposed lakebed of the GSL likely contributed 23% of total dust deposition and had the highest dust emissions per surface area. The other potential primary contributors were the Great Salt Lake Desert (45%) and the Sevier + Tule dry lakebeds (17%), both with lower per-area emissions. The impact on snowmelt, quantified by mass and energy balance modeling in the presence and absence of snow darkening by dust, was over two weeks (17 days) earlier. The impact of dust on snowmelt could have been more dramatic if the spring had been drier, but frequent snowfall buried dust layers, delaying dust-accelerated snowmelt later into the melt season.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels < 500 μm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/ perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions. This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH. It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice.

Background Treatment with monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) was found to reduce all-cause mortality in addition to cardiovascular events, suggesting pleiotropic effects. Eicosanoids are bioactive metabolites involved in cardiovascular disease and have not yet been studied in the course of PCSK9 inhibition. Methods In this prospective translational single-center study, plasma samples were collected from 64 patients before and after initiation of PCSK9 inhibitor treatment. Metabolomic analyses were performed using liquid chromatography coupled to high-resolution mass spectrometry. Results A total of 62 bioactive eicosanoids were detected. Among the metabolites, four were significantly decreased by PCSK9 inhibition after one month and remained stable after 6 months (figure): arachidonic acid (p=0.003), 12,13-DiHOME (p Conclusion PCSK9 inhibition leads to significant changes in the eicosanoid profile already after one month, in particular to a downregulation of arachidonic acid. This discovery complements the presumed pleiotropic effects of PCSK9 inhibition and may provide additional benefit in the treatment of atherosclerotic disease. Funding Acknowledgement Type of funding sources: None.

Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

Understanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations in KEL1 (P344T) and HSL7 (A695fs) that arose in an experimentally-evolved Saccharomyces cerevisiae population. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments we identified additional mutations that have positive genetic interactions with the kel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where the kel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in the kel1-P344T background. We reconstructed mutations in the ancestral and kel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors with KEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, and sheds light on a previously under-explored region of the yeast genetic interaction network.

Lichens and bryophytes are abundant primary producers in high latitude and high elevation ecosystems, and they play an important role in ecosystem processes such as decomposition and nutrient cycling. Despite their importance, little is known about the decomposability of lichens and bryophytes either among or within species, at the whole community level, or how this decomposability is affected by their functional traits. Here, we studied decomposability of lichens and bryophytes at the community-level and individual species-level (using 21 species and genera) collected from an elevational gradient in alpine Norway. In order to isolate the elevation effect on litter quality, we used a standardized laboratory bioassay to measure decomposability. In contrast to our expectations, we found that community-level decomposability of lichens and bryophytes increased with elevation and thus decreasing temperature. In contrast, phosphorus release from the litter decreased with elevation while nitrogen release was unresponsive. Decomposability was explained by nutrient concentrations, litter pH and primary producer group identity (lichens versus bryophytes) at both the individual species and community levels. Species turnover (changes in species composition and abundance) was the main driver of decomposability across elevation at the community level, despite some of the traits explaining decomposability showing high intraspecific variability. Our study highlights the importance of among-species variation in determining lichen and bryophyte decomposability. Further, the higher decomposability that we found for higher elevations suggests that global warming might result in a shift towards slower decomposable lichen and bryophyte species.

Galactose is a secondary fermentable sugar that requires specific regulatory and structural genes for its assimilation, which are under catabolite repression by glucose. When glucose is absent, the catabolic repression is attenuated, and the structuralGALgenes are fully activated. InSaccharomyces cerevisiae, theGALpathway is under selection in environments where galactose is present. However, it is unclear the adaptive strategies in response to long-term propagation in galactose as a sole carbon source in laboratory evolution experiments. Here, we performed a 4,000-generation evolution experiment using 48 diploidSaccharomyces cerevisiaepopulations to study adaptation in galactose. We show that fitness gains were greater in the galactose-evolved population than in identically evolved populations with glucose as a sole carbon source. Whole-genome sequencing of 96 evolved clones revealed recurrentde novosingle nucleotide mutations in candidate targets of selection, copy number variations, and ploidy changes. We find that most mutations that improve fitness in galactose lie outside of the canonicalGALpathway and are involved in nutrient signaling. Reconstruction of specific evolved alleles in candidate target of selection,SEC23andIRA1, showed a significant increase in fitness in galactose compared to glucose. In addition, most of our evolved populations (28/46; 61%) fixed aneuploidies on Chromosome VIII, suggesting a parallel adaptive amplification. Finally, we show greater loss of extrachromosomal elements in our glucose-evolved lineages compared with previous glucose evolution. Broadly, these data further our understanding of the evolutionary pressures that drive adaptation to less-preferred carbon sources.

Identification of adaptive targets in experimental evolution typically relies on extensive replication and genetic reconstruction. An alternative approach is to directly assay all mutations in an evolved clone by generating pools of segregants that contain random combinations of evolved mutations. Here, we apply this method to 6 Saccharomyces cerevisiae clones isolated from 4 diploid populations that were clonally evolved for 2,000 generations in rich glucose medium. Each clone contains 17–26 mutations relative to the ancestor. We derived intermediate genotypes between the founder and the evolved clones by bulk mating sporulated cultures of the evolved clones to a barcoded haploid version of the ancestor. We competed the resulting barcoded diploids en masse and quantified fitness in the experimental and alternative environments by barcode sequencing. We estimated average fitness effects of evolved mutations using barcode-based fitness assays and whole-genome sequencing for a subset of segregants. In contrast to our previous work with haploid evolved clones, we find that diploids carry fewer beneficial mutations, with modest fitness effects (up to 5.4%) in the environment in which they arose. In agreement with theoretical expectations, reconstruction experiments show that all mutations with a detectable fitness effect manifest some degree of dominance over the ancestral allele, and most are overdominant. Genotypes with lower fitness effects in alternative environments allowed us to identify conditions that drive adaptation in our system.

The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a nearly-identical homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1,000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease associated alleles.

The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles.

Identification of adaptive targets in experimental evolution typically relies on extensive replication and allele reconstructions. An alternative approach is to directly assay all mutations in an evolved clone by generating pools of segregants that contain random combinations of the evolved mutations. Here, we apply this method to 6 clones isolated from 4 diploid populations that were clonally evolved for 2,000 generations in rich glucose medium. Each clone contains ∼20-25 mutations relative to the ancestor. We derived intermediate genotypes between the founder and the evolved clones by bulk mating sporulated cultures of each evolved clone to a barcoded haploid version of the founder. We competed the barcoded segregants en masse and quantified the fitness of each barcode. We estimated average fitness effects of evolved mutations using barcode fitness and whole genome sequencing for a subset of segregants or time-course whole population whole genome sequencing. In contrast to our previous work in haploid populations, we find that diploids carry fewer evolved mutations with a detectable fitness effect (6%), contributing a modest fitness advantage (up to 5.4%). In agreement with theoretical expectations, reconstruction experiments show that all adaptive mutations manifest some degree of dominance over the ancestral allele, and most are overdominant. Competition assays under conditions that deviated from the evolutionary environment show that adaptive mutations are often pleiotropic.

Stroke associated with transcatheter aortic valve replacement (TAVR) is a potentially devastating complication. Until recently, the Sentinel™ Cerebral Protection System (CPS; Boston Scientific) has been the only commercially available device for mechanical prevention of TAVR-related stroke. However, its effectiveness is still undetermined. Methods Between January 2019 and August 2020 consecutive patients were randomly assigned to TAVR with or without Sentinel™ in a 1:1 fashion. We defined as primary endpoint clinically detectable cerebrovascular events within 72 hours after TAVR, and as secondary endpoints LOS and 12-month mortality. Logistic and linear regression analyses were used to assess associations of Sentinel™ use with endpoints. Results Of 411 patients (80±7 y/o, 47.4% female, EuroSCORE II 6.3±5.9%), Sentinel™ was used in 213 (51.8%), with both filters correctly deployed in 189 (46.0%). 20 (4.9%) cerebrovascular events were recorded, 10 (2.4%) of which were disabling strokes. Sentinel™ reduced cerebrovascular events in univariate analysis by 71% (OR 0.29, 95% CI 0.11–0.82; p=0.02) and after multivariate adjustment by 75% (adj. OR 0.25; 95% CI 0.08–0.80; p=0.02). Sentinel™ use was also significantly associated with shorter LOS (8.4±9.6 versus 6.7±6.1 days; p=0.03) and lower 12-month all-cause mortality (15.7% versus 7.5%, p=0.01). Conclusions In the present prospective all-comers TAVR cohort, Sentinel™ significantly 1) reduced cerebrovascular events, 2) shortened LOS, and 3) improved 12-month survival. These data promote the use of a CPS when implanting TAVR valves. Funding Acknowledgement Type of funding sources: None.

An empirical model is proposed for predicting layout dependent thickness variations in the semi-additive copper electrochemical plating (ECP) process. These variations are believed to be caused by the uneven depletion of copper sulfate during plating, causing low pattern density areas to plate faster than higher pattern density areas. Effective pattern density is extracted from the layout using a spatial filter and then mapped to the growth rates using a non-linear function. Test structures are designed that represent a wide range of feature sizes and pattern densities. After plating, these structures are profiled and used to fit the model, while other structures are used to validate its accuracy. Comparisons between the validation predictions and the experimental results show an average balanced root mean squared error (BRMSE) of 0.292 $\mu \text{m}$ , and a corresponding R2 value of 0.90. Fill patterns are then proposed and shown to control plating variations, by controlling pattern density. Finally, across-chip growth rate variations for a realistic interconnect layer are predicted, and experimentally confirmed.

ZusammenfassungDie Ende 2015 veröffentlichten ESC/ERS-Leitlinien und andere internationale Empfehlungen definierten die pulmonale Hypertonie (PH) bisher durch einen invasiv gemessenen mittleren pulmonal arteriellen Druck (mPAP) ≥ 25 mmHg in Ruhe. Auf dem 6th World Symposium on Pulmonary Hypertension in Nizza wurde eine Modifikation dieser hämodynamischen Definition im Sinne einer Senkung des Schwellenwertes auf > 20 mmHg vorgeschlagen. Für die präkapilläre PH wird zusätzlich ein pulmonaler Gefäßwiderstand (PVR) ≥ 3 Wood-Einheiten (WE) gefordert. Diese Änderung muss im Hinblick auf die zugrunde liegende Rationale und mögliche Konsequenzen kritisch hinterfragt werden; es bedarf daher einer eingehenden Erläuterung. Insbesondere muss klargestellt werden, dass diese Änderung aktuell keinen Einfluss auf die evidenzbasierte und zulassungskonforme Verschreibung von Medikamenten zur gezielten Therapie der pulmonal arteriellen Hypertonie (PAH) hat.

The relative contribution of bryophytes to plant diversity, primary productivity, and ecosystem functioning increases towards colder climates. Bryophytes respond to environmental changes at the species level, but because bryophyte species are relatively difficult to identify, they are often lumped into one functional group. Consequently, bryophyte function remains poorly resolved. Here, we explore how higher resolution of bryophyte functional diversity can be encouraged and implemented in tundra ecological studies. We briefly review previous bryophyte functional classifications and the roles of bryophytes in tundra ecosystems and their susceptibility to environmental change. Based on shoot morphology and colony organization, we then propose twelve easily distinguishable bryophyte functional groups. To illustrate how bryophyte functional groups can help elucidate variation in bryophyte effects and responses, we compiled existing data on water holding capacity, a key bryophyte trait. Although plant functional groups can mask potentially high interspecific and intraspecific variability, we found better separation of bryophyte functional group means compared with previous grouping systems regarding water holding capacity. This suggests that our bryophyte functional groups truly represent variation in the functional roles of bryophytes in tundra ecosystems. Lastly, we provide recommendations to improve the monitoring of bryophyte community changes in tundra study sites.

Loss of heterozygosity is a common mode of adaptation in asexual diploid populations. Because mitotic recombination frequently extends the full length of a chromosome arm, the selective benefit of loss of heterozygosity may be constrained by linked heterozygous mutations. In a previous laboratory evolution experiment with diploid yeast, we frequently observed homozygous mutations in the WHI2 gene on the right arm of Chromosome XV. However, when heterozygous mutations arose in the STE4 gene, another common target on Chromosome XV, loss of heterozygosity at WHI2 was not observed. Here we show that mutations at WHI2 are partially dominant and that mutations at STE4 are overdominant. We test whether beneficial heterozygous mutations at these two loci interfere with one another by measuring loss of heterozygosity at WHI2 over 1,000 generations for ∼300 populations that differed initially only at STE4 and WHI2. We show that the presence of an overdominant mutation in STE4 reduces, but does not eliminate, loss of heterozygosity at WHI2. By sequencing 40 evolved clones, we show that populations with linked overdominant and partially dominant mutations show less parallelism at the gene level, more varied evolutionary outcomes, and increased rates of aneuploidy. Our results show that the degree of dominance and the phasing of heterozygous beneficial mutations can constrain loss of heterozygosity along a chromosome arm, and that conflicts between partially dominant and overdominant mutations can affect evolutionary outcomes.SIGNIFICANCE STATEMENTIn diploid populations, it is beneficial for partially dominant beneficial mutations to lose heterozygosity, but it is deleterious for overdominant beneficial mutations to do so. Because loss-of-heterozygosity tracts often encompass entire chromosome arms, a conflict will arise when a partially dominant beneficial mutation and an overdominant beneficial mutation exist in close proximity. We demonstrate that this conflict occurs, and that it restricts loss of heterozygosity, resulting in more variable evolutionary outcomes.

BACKGROUND Mapping of T1 and T2 relaxation times in cardiac MRI is an invaluable tool for the diagnosis and risk stratification of a wide spectrum of cardiac diseases. PURPOSE To investigate the global and regional reproducibility of native T1 and T2 mapping and to analyze the influence of demographic factors, physiological parameters, slice position, and myocardial regions on reproducibility. STUDY TYPE Prospective single-center cohort-study. POPULATION Fifty healthy volunteers (29 female, 21 male) with a mean age of 39.4 ± 13.7 years. FIELD STRENGTH/SEQUENCE Each volunteer was investigated twice at 1.5 T using a modified look-locker inversion-recovery (MOLLI) sequence (T1 mapping) and a T2-prepared steady-state free precession (SSFP) sequence (T2 mapping). ASSESSMENT Global T1 and T2 values were quantified for the entire left ventricle in three short-axis slices. Regional T1 and T2 values were measured for each myocardial segment and for myocardial segments grouped by slice position and anatomical region. STATISTICAL TESTS Test-retest reproducibility was assessed using intraclass correlation coefficient (ICC) and Bland-Altman statistics. A P value

Question: Cold environments are stressful for vascular plants, and stress-tolerant non-vascular photoautotrophs, e.g. bryophytes and lichens, become relatively more important as competition from vascular plants decreases towards higher elevations. Under increasingly stressful climatic conditions, species assembly of vascular plants is commonly driven more by environmental filtering, and abiotic constraints may lead to increased similarity between species and thus low functional diversity. Because bryophytes and lichens are less constrained by harsh environments, environmental filtering may be less strong. Instead, reduced competition from vascular plants can potentially free up niche space for non-vascular vegetation. Therefore, we hypothesized that functional diversity of vascular plants, bryophytes and lichens are likely to show contrasting responses to elevation. Location: Finse Alpine Research Centre, Southern Norway. Methods: We utilized measurements of species abundance and functional traits of the three groups along a 500-m elevational gradient in alpine southern Norway and calculated multi-trait and single-trait functional dispersion. Results: Functional diversity of vascular plants declined with elevation, indicating increased environmental filtering. By contrast, functional diversity of lichens and bryophytes increased along the same gradient, suggesting they are less exposed to environmental filtering, in line with our hypothesis. Instead, they likely benefit from the lower abundance of vascular plants at higher elevation. Conclusions: Our findings suggest that different photoautotroph groups vary in how they respond to the same environmental gradient, which may contribute to contrasting community assembly processes across groups. These divergent responses likely occur because non-vascular vegetation differs from vascular plants in terms of nutrient acquisition and water economy strategies, meaning that they respond differently to the same factors. This highlights the need to explicitly consider bryophytes and lichens in community-level studies whenever these groups are abundant.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

It is widely accepted in biology that all life on Earth gradually evolved over billions of years from a single ancestor. Yet, there is still much about this process that is not fully understood. Evolution is often thought of as progressing in a linear fashion, with each new generation being better adapted to its environment than the last. But it has been proposed that evolution is also nontransitive: this means even if each generation is ‘fitter’ than its immediate predecessor, these series of adaptive changes will occasionally result in organisms that are less fit than their distant ancestors. Laboratory experiments of evolution are a good way to test evolutionary theories because they allow researchers to create scenarios that are impossible to observe in natural populations, such as an organism competing against its extinct ancestors. Buskirk et al. set up such an experiment using yeast to determine whether nontransitive effects can be observed in the direct descendants of an organism. At the start of the experiment, the yeast cells were host to a non-infectious ‘killer’ virus that is common among yeast. Cells containing the virus produce a toxin that destroys other yeast that lack the virus. The populations of yeast were given a nutrient-rich broth in which to grow and subjected to a simple evolutionary pressure: to grow fast, which limits the amount of resources available. As the yeast evolved, they gained beneficial genetic mutations that allowed them to outcompete their neighbors, and they passed these traits down to their descendants. Some of these mutations occurred not in the yeast genome, but in the genome of the killer virus, and this stopped the yeast infected with the virus from producing the killer toxin. Over time, other mutations resulted in the infected yeast no longer being immune to the toxin. Thus, when Buskirk et al. pitted these yeast against their distant ancestors, the new generation were destroyed by the toxins the older generation produced. These findings provide the first experimental evidence for nontransitivity along a line of descent. The results have broad implications for our understanding of how evolution works, casting doubts over the idea that evolution always involves a direct progression towards new, improved traits.