Cancerous time estimation for interpreting the evolution of lung adenocarcinoma.

The evolution of lung adenocarcinoma is accompanied by a multitude of gene mutations and dysfunctions, rendering its phenotypic state and evolutionary direction highly complex. To interpret the evolution of lung adenocarcinoma, various methods have been developed to elucidate the molecular pathogenesis and functional evolution processes. However, most of these methods are constrained by the absence of cancerous temporal information, and the challenges of heterogeneous characteristics. To handle these problems, in this study, a patient quasi-potential landscape method was proposed to estimate the cancerous time of phenotypic states' emergence during the evolutionary process. Subsequently, a total of 39 different oncogenetic paths were identified based on cancerous time and mutations, reflecting the molecular pathogenesis of the evolutionary process of lung adenocarcinoma. To interpret the evolution patterns of lung adenocarcinoma, three oncogenetic graphs were obtained as the common evolutionary patterns by merging the oncogenetic paths. Moreover, patients were evenly re-divided into early, middle, and late evolutionary stages according to cancerous time, and a feasible framework was developed to construct the functional evolution network of lung adenocarcinoma. A total of six significant functional evolution processes were identified from the functional evolution network based on the pathway enrichment analysis, which plays critical roles in understanding the development of lung adenocarcinoma.

Benefits and Limits of Phasing Alleles for Network Inference of Allopolyploid Complexes.

Accurately reconstructing the reticulate histories of polyploids remains a central challenge for understanding plant evolution. Although phylogenetic networks can provide insights into relationships among polyploid lineages, inferring networks may be hindered by the complexities of homology determination in polyploid taxa. We use simulations to show that phasing alleles from allopolyploid individuals can improve phylogenetic network inference under the multispecies coalescent by obtaining the true network with fewer loci compared with haplotype consensus sequences or sequences with heterozygous bases represented as ambiguity codes. Phased allelic data can also improve divergence time estimates for networks, which is helpful for evaluating allopolyploid speciation hypotheses and proposing mechanisms of speciation. To achieve these outcomes in empirical data, we present a novel pipeline that leverages a recently developed phasing algorithm to reliably phase alleles from polyploids. This pipeline is especially appropriate for target enrichment data, where the depth of coverage is typically high enough to phase entire loci. We provide an empirical example in the North American Dryopteris fern complex that demonstrates insights from phased data as well as the challenges of network inference. We establish that our pipeline (PATÉ: Phased Alleles from Target Enrichment data) is capable of recovering a high proportion of phased loci from both diploids and polyploids. These data may improve network estimates compared with using haplotype consensus assemblies by accurately inferring the direction of gene flow, but statistical nonidentifiability of phylogenetic networks poses a barrier to inferring the evolutionary history of reticulate complexes.

Sequential Bayesian Phylogenetic Inference.

The ideal approach to Bayesian phylogenetic inference is to estimate all parameters of interest jointly in a single hierarchical model. However, this is often not feasible in practice due to the high computational cost. Instead, phylogenetic pipelines generally consist of sequential analyses, whereby a single point estimate from a given analysis is used as input for the next analysis (e.g., a single multiple sequence alignment is used to estimate a gene tree). In this framework, uncertainty is not propagated from step to step, which can lead to inaccurate or spuriously confident results. Here, we formally develop and test a sequential inference approach for Bayesian phylogenetic inference, which uses importance sampling to generate observations for the next step of an analysis pipeline from the posterior distribution produced in the previous step. Our sequential inference approach presented here not only accounts for uncertainty between analysis steps but also allows for greater flexibility in software choice (and hence model availability) and can be computationally more efficient than the traditional joint inference approach when multiple models are being tested. We show that our sequential inference approach is identical in practice to the joint inference approach only if sufficient information in the data is present (a narrow posterior distribution) and/or sufficiently many important samples are used. Conversely, we show that the common practice of using a single point estimate can be biased, for example, a single phylogeny estimate can transform an unrooted phylogeny into a time-calibrated phylogeny. We demonstrate the theory of sequential Bayesian inference using both a toy example and an empirical case study of divergence-time estimation in insects using a relaxed clock model from transcriptome data. In the empirical example, we estimate 3 posterior distributions of branch lengths from the same data (DNA character matrix with a GTR+Γ+I substitution model, an amino acid data matrix with empirical substitution models, and an amino acid data matrix with the PhyloBayes CAT-GTR model). Finally, we apply 3 different node-calibration strategies and show that divergence time estimates are affected by both the data source and underlying substitution process to estimate branch lengths as well as the node-calibration strategies. Thus, our new sequential Bayesian phylogenetic inference provides the opportunity to efficiently test different approaches for divergence time estimation, including branch-length estimation from other software.

Shrinkage-based Random Local Clocks with Scalable Inference.

Molecular clock models undergird modern methods of divergence-time estimation. Local clock models propose that the rate of molecular evolution is constant within phylogenetic subtrees. Current local clock inference procedures exhibit one or more weaknesses, namely they achieve limited scalability to trees with large numbers of taxa, impose model misspecification, or require a priori knowledge of the existence and location of clocks. To overcome these challenges, we present an autocorrelated, Bayesian model of heritable clock rate evolution that leverages heavy-tailed priors with mean zero to shrink increments of change between branch-specific clocks. We further develop an efficient Hamiltonian Monte Carlo sampler that exploits closed form gradient computations to scale our model to large trees. Inference under our shrinkage clock exhibits a speed-up compared to the popular random local clock when estimating branch-specific clock rates on a variety of simulated datasets. This speed-up increases with the size of the problem. We further show our shrinkage clock recovers known local clocks within a rodent and mammalian phylogeny. Finally, in a problem that once appeared computationally impractical, we investigate the heritable clock structure of various surface glycoproteins of influenza A virus in the absence of prior knowledge about clock placement. We implement our shrinkage clock and make it publicly available in the BEAST software package.

A molecular phylogeny of the Petaluridae (Odonata: Anisoptera): A 160-Million-Year-Old story of drift and extinction.

Petaluridae (Odonata: Anisoptera) is a relict dragonfly family, having diverged from its sister family in the Jurassic, of eleven species that are notable among odonates (dragonflies and damselflies) for their exclusive use of fen and bog habitats, their burrowing behavior as nymphs, large body size as adults, and extended lifespans. To date, several nodes within this family remain unresolved, limiting the study of the evolution of this peculiar family. Using an anchored hybrid enrichment dataset of over 900 loci we reconstructed the species tree of Petaluridae. To estimate the temporal origin of the genera within this family, we used a set of well-vetted fossils and a relaxed molecular clock model in a divergence time estimation analysis. We estimate that Petaluridae originated in the early Cretaceous and confirm the existence of monophyletic Gondwanan and Laurasian clades within the family. Our relaxed molecular clock analysis estimated that these clades diverged from their MRCA approximately 160 mya. Extant lineages within this family were identified to have persisted from 6 (Uropetala) to 120 million years (Phenes). Our biogeographical analyses focusing on a set of key regions suggest that divergence within Petaluridae is largely correlated with continental drift, the exposure of land bridges, and the development of mountain ranges. Our results support the hypothesis that species within Petaluridae have persisted for tens of millions of years, with little fossil evidence to suggest widespread extinction in the family, despite optimal conditions for the fossilization of nymphs. Petaluridae appear to be a rare example of habitat specialists that have persisted for tens of millions of years.

Phylogenetic insights into the Salicaceae: The evolution of willows and beyond.

The Salicaceae includes approximately 54 genera and over 1,400 species with a cosmopolitan distribution. Members of the family are well-known for their diverse secondary plant metabolites, and they play crucial roles in tropical and temperate forest ecosystems. Phylogenetic reconstruction of the Salicaceae has been historically challenging due to the limitations of molecular markers and the extensive history of hybridization and polyploidy within the family. Our study employs whole-genome sequencing of 74 species to generate an extensive phylogeny of the Salicaceae. We generated two RAD-Seq enriched whole-genome sequence datasets and extracted two additional gene sets corresponding to the universal Angiosperms353 and Salicaceae-specific targeted-capture arrays. We reconstructed maximum likelihood-based molecular phylogenies using supermatrix and coalescent-based supertree approaches. Our fossil-calibrated phylogeny estimates that the Salicaceae originated around 128 million years ago and unravels the complex taxonomic relationships within the family. Our findings confirm the non-monophyly of the subgenus Salix s.l. and further support the merging of subgenera Chamaetia and Vetrix, both of which exhibit intricate patterns within and among different sections. Overall, our study not only enhances our understanding of the evolution of the Salicaceae, but also provides valuable insights into the complex relationships within the family.

Reticulate evolution: Detection and utility in the phylogenomics era.

Phylogenomics has enriched our understanding that the Tree of Life can have network-like or reticulate structures among some taxa and genes. Two non-vertical modes of evolution - hybridization/introgression and horizontal gene transfer - deviate from a strictly bifurcating tree model, causing non-treelike patterns. However, these reticulate processes can produce similar patterns to incomplete lineage sorting or recombination, potentially leading to ambiguity. Here, we present a brief overview of a phylogenomic workflow for inferring organismal histories and compare methods for distinguishing modes of reticulate evolution. We discuss how the timing of coalescent events can help disentangle introgression from incomplete lineage sorting and how horizontal gene transfer events can help determine the relative timing of speciation events. In doing so, we identify pitfalls of certain methods and discuss how to extend their utility across the Tree of Life. Workflows, methods, and future directions discussed herein underscore the need to embrace reticulate evolutionary patterns for understanding the timing and rates of evolutionary events, providing a clearer view of life's history.

Scalable Bayesian Divergence Time Estimation With Ratio Transformations.

Divergence time estimation is crucial to provide temporal signals for dating biologically important events from species divergence to viral transmissions in space and time. With the advent of high-throughput sequencing, recent Bayesian phylogenetic studies have analyzed hundreds to thousands of sequences. Such large-scale analyses challenge divergence time reconstruction by requiring inference on highly correlated internal node heights that often become computationally infeasible. To overcome this limitation, we explore a ratio transformation that maps the original $N-1$ internal node heights into a space of one height parameter and $N-2$ ratio parameters. To make the analyses scalable, we develop a collection of linear-time algorithms to compute the gradient and Jacobian-associated terms of the log-likelihood with respect to these ratios. We then apply Hamiltonian Monte Carlo sampling with the ratio transform in a Bayesian framework to learn the divergence times in 4 pathogenic viruses (West Nile virus, rabies virus, Lassa virus, and Ebola virus) and the coralline red algae. Our method both resolves a mixing issue in the West Nile virus example and improves inference efficiency by at least 5-fold for the Lassa and rabies virus examples as well as for the algae example. Our method now also makes it computationally feasible to incorporate mixed-effects molecular clock models for the Ebola virus example, confirms the findings from the original study, and reveals clearer multimodal distributions of the divergence times of some clades of interest.

Young evolutionary origins of dioecy in the genus Asparagus.

PREMISE: Dioecy (separate sexes) has independently evolved numerous times across the angiosperm phylogeny and is recently derived in many lineages. However, our understanding is limited regarding the evolutionary mechanisms that drive the origins of dioecy in plants. The recent and repeated evolution of dioecy across angiosperms offers an opportunity to make strong inferences about the ecological, developmental, and molecular factors influencing the evolution of dioecy, and thus sex chromosomes. The genus Asparagus (Asparagaceae) is an emerging model taxon for studying dioecy and sex chromosome evolution, yet estimates for the age and origin of dioecy in the genus are lacking. METHODS: We use plastome sequences and fossil time calibrations in phylogenetic analyses to investigate the age and origin of dioecy in the genus Asparagus. We also review the diversity of sexual systems present across the genus to address contradicting reports in the literature. RESULTS: We estimate that dioecy evolved once or twice approximately 2.78-3.78 million years ago in Asparagus, of which roughly 27% of the species are dioecious and the remaining are hermaphroditic with monoclinous flowers. CONCLUSIONS: Our findings support previous work implicating a young age and the possibility of two origins of dioecy in Asparagus, which appear to be associated with rapid radiations and range expansion out of Africa. Lastly, we speculate that paleoclimatic oscillations throughout northern Africa may have helped set the stage for the origin(s) of dioecy in Asparagus approximately 2.78-3.78 million years ago.

Hypothermic sepsis in time since death estimation - a case report.

Both hyper- and hypothermia are problematic in temperature based forensic time since death estimation. Hyperthermia may occur in infection, traumatic brain injury, and intoxication. Hypothermia is encountered predominantly in exposure. Sepsis may present itself clinically as hypothermic. Sepsis is not uncommon in the forensic setting and mostly occurs in the context of malpractice accusations. There is usually little overlap between sepsis and typical forensic time since death estimation scenarios of violent or otherwise suspicious deaths. In the presented case, hypothermia and time since death estimations did collide. An inmate was found dead in his jail cell. Wardens claimed they had visually approached him alive relatively shortly prior. Rectal temperature measurements, using two separate crime scene thermometers as well as temperature loggers, revealed low rectal temperature at relatively high ambient temperature. These findings suggested a much longer postmortem interval and consequently raised doubts about the stated timeline. The wardens' claims were however confirmed by camera recordings, which also allowed a reasonable estimate of the true time of death. The cause of death was confirmed as septic organ failure at autopsy, which explained low rectal temperature. The presence of WISCHNEWSKI-spots was noted. When the PRISM-method was applied to the temperature recordings, low rectal temperature at the time of death was detected successfully. However, adaptation of the underlying equation for lower "starting temperature" did not produce satisfactory results. It is concluded that even though hypothermia at the time of death may possibly be detected from temperature data, attempts at time since death estimation for cases of hypothermia by adaptation of the equation should be avoided.

Accuracy of patient-reported spell duration: A comparative study.

Clinicians rely heavily on patient histories to make medical diagnoses, most of which are inherently subjective and prone to inaccuracies. The aim of this study is to compare the subjective versus objective duration of spells through a retrospective chart review of patients admitted to the epilepsy monitoring unit at our tertiary care medical center. One hundred patients were analyzed. Differences in the accuracy of subjective estimations versus objective duration were compared by age, sex, focal versus generalized, location (frontal versus non-frontal), and spell type (focal aware versus impaired awareness and epileptic versus non-epileptic). Our data show that patients are poor subjective estimators, with 73% of patients overestimating the duration of their spells. We did not find differences in estimated duration by age, sex, seizure location or spell type. A notable exception was patients with generalized convulsive seizures, who accurately reported spell duration to within 17 s. This is likely because these seizures are stereotypical, and patients/family time them. Moreover, patients with non-epileptic spells were worse estimators of their spell duration than those with epileptic spells. In addition, although the prefrontal lobe plays a role in time estimation, we did not find that patients with frontal lobe seizures were worse estimators than those with non-frontal seizures, but invasive monitoring can more precisely localize seizures within areas of the frontal lobe responsible for time estimation. Our data emphasize the importance of not relying solely on patient-reported time estimation in diagnosing and developing treatment plans and instead instructing patients to time their spells.

Differences in time perception in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a condition that occurs due to complete (apnea) and partial (hypopnea) obstruction in the upper airways during sleep. Hypoxia is one of the key factors contributing to the development of symptoms of obstructive sleep apnea and OSA-related diseases. OBJECTIVE: The present study aimed to evaluate time perception differences between patients with OSA and healthy individuals, as well as among different OSA severity groups. METHODS: Twenty severe OSA, twenty moderate OSA, twenty mild OSA patients, and twenty healthy volunteers without OSA were included in the study. Scales were administered to the participants. Time perception tests were administered to evaluate perceptual timing. RESULTS: In the paced motor timing test, a difference was observed between the OSA ( +) group and the OSA (-) group. In the Time Estimation Test, a difference was observed between the OSA ( +) group and the OSA (-) group and their subgroups. CONCLUSION: The internal clock works slower in the OSA ( +) group. When subgroups were compared based on the degree of OSA, the internal clock worked slower as we transitioned from the OSA (-) group to the severe OSA group. It is considered that as you move from the OSA (-) group to the severe OSA group, the switch between pacemaker and accumulator is disrupted due to the decrease in attention. Recurrent hypoxia observed in OSA may alter the perception of time by affecting attention.

A global phylogeny of turtles reveals a burst of climate-associated diversification on continental margins.

Living turtles are characterized by extraordinarily low species diversity given their age. The clade's extensive fossil record indicates that climate and biogeography may have played important roles in determining their diversity. We investigated this hypothesis by collecting a molecular dataset for 591 individual turtles that, together, represent 80% of all turtle species, including representatives of all families and 98% of genera, and used it to jointly estimate phylogeny and divergence times. We found that the turtle tree is characterized by relatively constant diversification (speciation minus extinction) punctuated by a single threefold increase. We also found that this shift is temporally and geographically associated with newly emerged continental margins that appeared during the Eocene-Oligocene transition about 30 million years before present. In apparent contrast, the fossil record from this time period contains evidence for a major, but regional, extinction event. These seemingly discordant findings appear to be driven by a common global process: global cooling and drying at the time of the Eocene-Oligocene transition. This climatic shift led to aridification that drove extinctions in important fossil-bearing areas, while simultaneously exposing new continental margin habitat that subsequently allowed for a burst of speciation associated with these newly exploitable ecological opportunities.

Distributed NN-Based Formation Control of Multi-Agent Systems: A Reduced-Order Appointed-Time Observer Approach.

Although the formation control of multi-agent systems has been widely investigated from various aspects, the problem is still not well resolved, especially for the case of distributed output-feedback formation controller design without input information exchange among neighboring agents. Using relative output information, this paper presents a novel distributed reduced-order estimation of the formation error at a predefined time. Based on the proposed distributed observer, a neural-network-based formation controller is then designed for multi-agent systems with connected graphs. The results are verified by both theoretical demonstration and simulation example.

Virtual Sensing of Key Variables in the Hydrogen Production Process: A Comparative Study of Data-Driven Models.

Hydrogen is an ideal energy carrier manufactured mainly by the natural gas steam reforming hydrogen production process. The concentrations of CH4, CO, CO2, and H2 in this process are key variables related to product quality, which thus need to be controlled accurately in real-time. However, conventional measurement methods for these concentrations suffer from significant delays or huge acquisition and upkeep costs. Virtual sensors effectively compensate for these shortcomings. Unfortunately, previously developed virtual sensors have not fully considered the complex characteristics of the hydrogen production process. Therefore, a virtual sensor model, called "moving window-based dynamic variational Bayesian principal component analysis (MW-DVBPCA)" is developed for key gas concentration estimation. The MW-DVBPCA considers complicated characteristics of the hydrogen production process, involving dynamics, time variations, and transportation delays. Specifically, the dynamics are modeled by the finite impulse response paradigm, the transportation delays are automatically determined using the differential evolution algorithm, and the time variations are captured by the moving window method. Moreover, a comparative study of data-driven virtual sensors is carried out, which is sporadically discussed in the literature. Meanwhile, the performance of the developed MW-DVBPCA is verified by the real-life natural gas steam reforming hydrogen production process.

A new discovery of cryptic species in barred sand burrower Limnichthys fasciatus (Pisces: Creediidae) from the western Pacific, with evolutionary perspectives of anti-equatorial species.

Although the barred sand burrower, Limnichthys fasciatus, is widely distributed throughout the western Pacific, including Japan, Taiwan, and Australia, its morphology and genetics are poorly known. We discovered four cryptic species of Limnichthys from the western Pacific based on mtDNA cytochrome c oxidase subunit I (COI) and 16S ribosomal RNA (rRNA) sequences. Genetic distances showed remarkably large differences (12.7%-24.3% in COI and 7.9%-19.6% in 16S rRNA) between true L. fasciatus (type locality: southeastern Australia) and the others. A relaxed clock model with optimized selected substitution models showed that their deep divergence began in the middle Miocene epoch and subsequently diverged into the current cryptic species in the Plio-Pleistocene. A eurythermal common ancestor may have evolved independently in each region due to geographical events and paleoclimatic fluctuations, which made it possible for L. fasciatus complex to be an anti-equatorial species. Despite their deep genetic divergence, they showed marked phenotypic similarity, suggesting that they have experienced similar selective pressures related to their specific behavior.

Molecular Clocks without Rocks: New Solutions for Old Problems.

Molecular data have been used to date species divergences ever since they were described as documents of evolutionary history in the 1960s. Yet, an inadequate fossil record and discordance between gene trees and species trees are persistently problematic. We examine how, by accommodating gene tree discordance and by scaling branch lengths to absolute time using mutation rate and generation time, multispecies coalescent (MSC) methods can potentially overcome these challenges. We find that time estimates can differ - in some cases, substantially - depending on whether MSC methods or traditional phylogenetic methods that apply concatenation are used, and whether the tree is calibrated with pedigree-based mutation rates or with fossils. We discuss the advantages and shortcomings of both approaches and provide practical guidance for data analysis when using these methods.

Phylogeny, biogeography, and character evolution of the genus Sophora s.l. (Fabaceae, Papilionoideae).

The papilionoid legume genus Sophora (Fabaceae) exhibits a worldwide distribution, but a phylogenetic framework to understand the evolution of this group is lacking to date. Previous studies have demonstrated that Sophora is not monophyletic and might include Ammodendron, Ammothamnus, and Echinosophora, but the relationships among these four genera (defined as Sophora s.l.) are unclear. Here we used a nuclear DNA dataset (ETS, ITS, SQD1) and a plastid DNA dataset (matK, rbcL, rpl32-trnL, trnL-F) of 654 accession sequences to reconstruct the phylogenetic relationships, estimate the divergence times and ancestral range of Sophora s.l., and infer the evolution of chromosome number and morphological characteristics. Our major aim was to reconstruct phylogenetic relationships to test monophyly and elucidate relationships within the genus. Our results indicated that Ammodendron, Ammothamnus, and Echinosophora are embedded within Sophora s.s. and that nine well-supported clades can be recognized within comprise Sophora s.l. Ancestral character state estimation revealed that the most recent common ancestor of Sophora s.l. was a deciduous shrub that lacks rhizome spines and has unwinged legumes. Divergence times estimation and ancestral area reconstruction showed that Sophora s.l. originated in Central Asia and/or adjacent Southeast China in the early Oligocene (ca. 31 Mya) and dispersed from these regions into East and South Asia's adjacent areas and North America via the Bering land bridge. The analyses also supported a South American origin for S. sect. Edwardsia, which experienced rapid radiation with its major lineages diversifying over a relatively narrow timescale (8 Mya).

Mnemonic Content and Hippocampal Patterns Shape Judgments of Time.

Our experience of time can feel dilated or compressed, rather than reflecting true "clock time." Although many contextual factors influence the subjective perception of time, it is unclear how memory accessibility plays a role in constructing our experience of and memory for time. Here, we used a combination of behavioral and functional MRI measures in healthy young adults (N = 147) to ask the question of how memory is incorporated into temporal duration judgments. Behaviorally, we found that event boundaries, which have been shown to disrupt ongoing memory integration processes, result in the temporal compression of duration judgments. Additionally, using a multivoxel pattern similarity analysis of functional MRI data, we found that greater temporal pattern change in the left hippocampus within individual trials was associated with longer duration judgments. Together, these data suggest that mnemonic processes play a role in constructing representations of time.

How many hours do you sleep? A comparison of subjective and objective sleep duration measures in a sample of insomnia patients and good sleepers.

Our objective was to assess the agreement and linear relationships amongst multiple measures of sleep duration in a sample of patients with insomnia disorder and good sleeper controls. We retrospectively analysed data from 123 patients with insomnia disorder and 123 age- and gender-matched good sleeper controls who completed a simple subjective habitual sleep duration question (Pittsburgh Sleep Quality Index), a sleep diary (5-14 days), 2 nights of polysomnography, and two corresponding morning subjective estimates of sleep duration. Descriptive statistics, linear regression analyses and Bland-Altman plots were used to describe the relationship and (dis)agreement between sleep duration measures. Relationships between polysomnography and the simple question as well as between polysomnography and sleep diary were weak to non-existent. Subjective measures and polysomnography did not agree. Sleep duration measured with the Pittsburgh Sleep Quality Index or sleep diary was about 2 hr above or up to 4 hr below polysomnography-measured sleep duration. Patients with insomnia disorder, on average, reported shorter sleep duration compared with polysomnography, while good sleeper controls, on average, reported longer sleep duration compared with polysomnography. The results suggest that subjective and objective measures apparently capture different aspects of sleep, even when nominally addressing the same value (sleep duration). They disagree in both patients with insomnia disorder and good sleeper controls, but in different directions. Studies assessing sleep duration should take into account both the investigated population and the assessment method when interpreting results. Future studies should continue to investigate possible psychological and physiological correlates of sleep (mis)perception.