Binary-state speciation and extinction method is conditionally robust to realistic violations of its assumptions

Phylogenetic comparative methods allow us to test evolutionary hypotheses without the benefit of an extensive fossil record. These methods, however, make simplifying assumptions, among them that clades are always increasing or stable in diversity, an assumption we know to be false. This study simulates hypothetical clades to test whether the Binary State Speciation and Extinction (BiSSE) method can be used to correctly detect relative differences in diversification rate between ancestral and derived character states even as net diversification rates are declining overall. We simulate clades with declining but positive diversification rates, as well those in which speciation rates decline below extinction rates so that they are losing richness for part of their history. We run these analyses both with simulated symmetric and asymmetric speciation rates to test whether BiSSE can be used to detect them correctly. For simulations with a neutral character, the fit for a BiSSE model with a neutral character is better than alternative models so long as net diversification rates remain positive. Once net diversification rates become negative, the BiSSE model with the greatest likelihood often has a non-neutral character, even though there is no such character in the simulation. BiSSE’s usefulness in detecting real asymmetry in speciation rates improves with clade age, even well after net diversification rates have become negative. BiSSE is most useful in analyzing clades of intermediate age, before they have reached peak diversity and gone into decline. After this point, users of BiSSE risk incorrectly inferring differential evolutionary rates when none exist. Fortunately, most studies using BiSSE and similar models focus on rapid, recent diversifications, and are less likely to encounter the biases BiSSE models are subject to for older clades. For extant groups that were once more diverse than now, however, caution should be taken in inferring past diversification patterns without fossil data

Predicting outcomes of steady-state 13C isotope tracing experiments using Monte Carlo sampling

<p>Abstract</p> <p>Background</p> <p>Carbon-13 (¹³C) analysis is a commonly used method for estimating reaction rates in biochemical networks. The choice of carbon labeling pattern is an important consideration when designing these experiments. We present a novel Monte Carlo algorithm for finding the optimal substrate input label for a particular experimental objective (flux or flux ratio). Unlike previous work, this method does not require assumption of the flux distribution beforehand.</p> <p>Results</p> <p>Using a large <it>E. coli </it>isotopomer model, different commercially available substrate labeling patterns were tested computationally for their ability to determine reaction fluxes. The choice of optimal labeled substrate was found to be dependent upon the desired experimental objective. Many commercially available labels are predicted to be outperformed by complex labeling patterns. Based on Monte Carlo Sampling, the dimensionality of experimental data was found to be considerably less than anticipated, suggesting that effectiveness of ¹³C experiments for determining reaction fluxes across a large-scale metabolic network is less than previously believed.</p> <p>Conclusions</p> <p>While ¹³C analysis is a useful tool in systems biology, high redundancy in measurements limits the information that can be obtained from each experiment. It is however possible to compute potential limitations before an experiment is run and predict whether, and to what degree, the rate of each reaction can be resolved.</p

Floral and environmental gradients on a Late Cretaceous landscape

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116378/1/ecm201282123.pd

A reductive aminase from Aspergillus oryzae

Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) which can catalyse the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalysing imine formation as well as reduction. Crystal structures of AspRedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient (R)-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover numbers of up to 32,000 and space time yields up to 3.73 g L-1 d-1

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males

A novel simplified biomechanical assessment of the heel pad during foot plantarflexion

International audienc

Epochs, events and episodes: Marking the geological impact of humans

Event stratigraphy is used to help characterise the Anthropocene as a chronostratigraphic concept, based on analogous deep-time events, for which we provide a novel categorization. Events in stratigraphy are distinct from extensive, time-transgressive ‘episodes’ – such as the global, highly diachronous record of anthropogenic change, termed here an Anthropogenic Modification Episode (AME). Nested within the AME are many geologically correlatable events, the most notable being those of the Great Acceleration Event Array (GAEA). This isochronous array of anthropogenic signals represents brief, unique events evident in geological deposits, e.g.: onset of the radionuclide ‘bomb-spike’; appearance of novel organic chemicals and fuel ash particles; marked changes in patterns of sedimentary deposition, heavy metal contents and carbon/nitrogen isotopic ratios; and ecosystem changes leaving a global fossil record; all around the mid-20th century. The GAEA reflects a fundamental transition of the Earth System to a new state in which many parameters now lie beyond the range of Holocene variability. Globally near-instantaneous events can provide robust primary guides for chronostratigraphic boundaries. Given the intensity, magnitude, planetary significance and global isochroneity of the GAEA, it provides a suitable level for recognition of the base of the Anthropocene as a series/epoch

Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction

Importance  The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. Objective  To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Design, Setting, and Participants  Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Main Outcomes and Measures  Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. Results  The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of$45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to$75 301 per QALY. Conclusions and Relevance  For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril

Response to Merritts et al. (2023): The Anthropocene is complex. Defining it is not

Merritts et al. (2023) misrepresent Paul Crutzen’s Anthropocene concept as encompassing all significant anthropogenic impacts, extending back many millennia. Crutzen's definition reflects massively enhanced, much more recent human impacts that transformed the Earth System away from the stability of Holocene conditions. His concept of an epoch (hence the ‘cene’ suffix) is more consistent with the strikingly distinct sedimentary record accumulated since the mid-20th century. Waters et al. (2022) highlighted a Great Acceleration Event Array (GAEA) of stratigraphic event markers that are indeed diverse and complex but also tightly clustered around 1950 CE, allowing ultra-high resolution characterization and correlation of a clearly recognisable Anthropocene chronostratigraphic base. The ‘Anthropocene event’ offered by Merritts et al., following Gibbard et al. (2021, 2022), is a highly nuanced concept that obfuscates the transformative human impact of the chronostratigraphic Anthropocene. Waters et al. (2022) restricted the meaning of the term ‘event’ in geology to conform with usual Quaternary practice and improve its utility. They simultaneously recognized an evidence-based Anthropogenic Modification Episode that is more explicitly defined than the highly interpretive interdisciplinary ‘Anthropocene event’ of Gibbard et al. (2021, 2022). The advance of science is best served through clearly developed concepts supported by tightly circumscribed terminology; indeed, improvements to stratigraphy over recent decades have been achieved through increasingly precise definitions, especially for chronostratigraphic units, and not by retaining vague terminology