Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two‐stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous

A systematic review of local vulnerability to climate change: in search of transparency, coherence and comparability

Because vulnerability is a conceptual construct rather than a directly observable phenomenon, most vulnerability assessments measure a set of “vulnerability indicators”. In order to identify the core approaches and range of variation in the field, we conducted a systematic literature review on local vulnerability to climate change. The systematic review entailed an identification of frameworks, concepts, and operationalizations and a transparency assessment of their reporting. Three fully defined relevant frameworks of vulnerability were identified: IPCC, Patterns of Smallholder Vulnerability and Vulnerability as Expected Poverty. Comparative analysis found substantial heterogeneity in frameworks, concepts and operationalizations, making it impossible to identify patterns of climate vulnerability indicators and determinants that have robust empirical support. If research measuring farmers’ vulnerability to climate change is to have any comparability, it needs greater conceptual coherence and empirical validity. We recommend a systematic program of testing and validating vulnerability measures before institutionalizing them in programmatic contexts

Functional trade-offs in cribellate silk mediated by spinning behavior

Web-building spiders are an extremely diverse predatory group due to their use of physiologically differentiated silk types in webs. Major shifts in silk functional properties are classically attributed to innovations in silk genes and protein expression. Here, we disentangle the effects of spinning behavior on silk performance of the earliest types of capture threads in spider webs for the first time. Progradungula otwayensis produces two variations of cribellate silk in webs: ladder lines are stereotypically combed with the calamistrum while supporting rail lines contain silk that is naturally uncombed, spun without the intervention of the legs. Combed cribellate silk is highly extensible and adhesive suggesting that the reserve warp and cribellate fibrils brings them into tension only near or after the underlying axial fibers are broken. In contrast, these three fiber components are largely aligned in the uncombed threads and deform as a single composite unit that is 5–10x stronger, but significantly less adhesive, allowing them to act as structural elements in the web. Our study reveals that cribellate silk can occupy a surprisingly diverse performance space, accessible through simple changes in spider behavior, which may have facilitated the impressive diversification of web architectures utilizing this ancient silk.Fil: Michalik, Peter. ERNST MORITZ ARNDT UNIVERSITÄT GREIFSWALD (UG);Fil: Piorkowski, Dakota. Tunghai University; ChinaFil: Blackledge, Todd A.. University of Akron; Estados UnidosFil: Ramirez, Martin Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

AlphaFold predicts the most complex protein knot and composite protein knots

The computer artificial intelligence system AlphaFold has recently predicted previously unknown three-dimensional structures of thousands of proteins. Focusing on the subset with high-confidence scores, we algorithmically analyze these predictions for cases where the protein backbone exhibits rare topological complexity, i.e. knotting. Amongst others, we discovered a $7_1$-knot, the most topologically complex knot ever found in a protein, as well several 6-crossing composite knots comprised of two methyltransferase or carbonic anhydrase domains, each containing a simple trefoil knot. These deeply embedded composite knots occur evidently by gene duplication and interconnection of knotted dimers. Finally, we report two new five-crossing knots including the first $5_1$-knot. Our list of analyzed structures forms the basis for future experimental studies to confirm these novel knotted topologies and to explore their complex folding mechanisms.Comment: This article appeared openly accessible in M. A. Brems et al., Protein Science. 2022; 31( 8):e4380 and may be found at https://doi.org/10.1002/pro.438

Temporal variation in macroalgal removal: insights from an impacted equatorial coral reef system

Macroalgal removal is a critical ecosystem function yet few studies have considered its temporal variability, especially on impacted reefs with limited herbivorous fish biodiversity. To address this, we quantified macroalgal removal and mass-standardised bite rates of herbivorous fishes monthly from July 2016 to June 2017 using a series of transplanted Sargassum ilicifolium assays and underwater video cameras on three degraded coral reefs in Singapore: Pulau Satumu, Kusu Island, and Terumbu Pempang Tengah. Our results revealed a distinct temporal pattern in macroalgal herbivory (proportion of biomass removed and mass-standardised bite rates) rates across all sites, increasing from July and decreasing from January, with the highest rates recorded in December (28.10 ± 3.05 g 3.5 h−1; 208.24 ± 29.99 mass-standardised bites 3.5 h−1) and the lowest in May (0.86 ± 0.17 g 3.5 h−1; 9.55 ± 3.19 mass-standardised bites 3.5 h−1). These coincided with the S. ilicifolium growth cycle, confirming previous evidence that herbivory rates are closely linked to macroalgal condition. Video analyses revealed nine species feeding over a year (31,839 bites; 8702.89 mass-standardised bites), with Siganus virgatus responsible for ∼ 80% of the total mass-standardised bites. Siganus virgatus took the largest proportion of bites monthly, except between April and June, when Scarus rivulatus was dominant, suggesting temporal constraints in functional roles