Modeling Pulsed Evolution and Time-Independent Variation Improves the Confidence Level of Ancestral and Hidden State Predictions.

Ancestral state reconstruction is not only a fundamental tool for studying trait evolution, but also very useful for predicting the unknown trait values (hidden states) of extant species. A well-known problem in ancestral and hidden state predictions is that the uncertainty associated with predictions can be so large that predictions themselves are of little use. Therefore, for meaningful interpretation of predicted traits and hypothesis testing, it is prudent to accurately assess the uncertainty of the predictions. Commonly used constant-rate Brownian motion (BM) model fails to capture the complexity of tempo and mode of trait evolution in nature, making predictions under the BM model vulnerable to lack-of-fit errors from model misspecification. Using empirical data (mammalian body size and bacterial genome size), we show that the distribution of residual Z-scores under the BM model is neither homoscedastic nor normal as expected. Consequently, the 95% confidence intervals of predicted traits are so unreliable that the actual coverage probability ranges from 33% (strongly permissive) to 100% (strongly conservative). Alternative methods such as BayesTraits and StableTraits that allow variable rates in evolution improve the predictions but are computationally expensive. Here, we develop Reconstructing Ancestral State under Pulsed Evolution in R by Gaussian Decomposition (RasperGade), a method of ancestral and hidden state prediction that uses the Levy process to explicitly model gradual evolution, pulsed evolution, and time-independent variation. Using the same empirical data, we show that RasperGade outperforms both BayesTraits and StableTraits in providing reliable confidence estimates and is orders-of-magnitude faster. Our results suggest that, when predicting the ancestral and hidden states of continuous traits, the rate variation should always be assessed and the quality of confidence estimates should always be examined. [Bacterial genomic traits; model misspecification; trait evolution.].

Model Checking Fuzzy Computation Tree Logic Based on Fuzzy Decision Processes with Cost.

In order to solve the problems in fuzzy computation tree logic model checking with cost operator, we propose a fuzzy decision process computation tree logic model checking method with cost. Firstly, we introduce a fuzzy decision process model with cost, which can not only describe the uncertain choice and transition possibility of systems, but also quantitatively describe the cost of the systems. Secondly, under the model of the fuzzy decision process with cost, we give the syntax and semantics of the fuzzy computation tree logic with cost operators. Thirdly, we study the problem of computation tree logic model checking for fuzzy decision process with cost, and give its matrix calculation method and algorithm. We use the example of medical expert systems to illustrate the method and model checking algorithm.

The haplotypes of various TNF related genes associated with scleritis in Chinese Han.

BACKGROUND: Several studies have stated that TNF-α participates in the pathogenesis of scleritis, but also in several systemic autoimmune diseases and vasculitis, of which some are associated with scleritis. Earlier GWAS and SNP studies have confirmed that multiple SNPs of TNF related genes are associated with many immune-mediated disorders. The purpose of this study was to examine the association of TNF related gene polymorphisms with scleritis in Chinese Han. A case-control study was carried out in 556 non-infectious scleritis cases and 742 normal controls. A total of 28 single-nucleotide polymorphisms (SNPs) were genotyped by the iPLEXGold genotyping assay. RESULTS: No significant correlations were seen between the individual SNPs in the TNF related genes and scleritis. Haplotype analysis showed a significantly decreased frequency of a TNFAIP3 TGT haplotype (order of SNPs: rs9494885, rs3799491, rs2230926) (Pc = 0.021, OR = 0.717, 95% CI = 0.563-0.913) and a significantly increased frequency of a TNFSF4 GT haplotype (order of SNPs: rs3850641, rs704840) (Pc = 0.004, OR = 1.691, 95% CI = 1.205-2.372) and TNFSF15 CCC haplotype (order of SNPs: rs6478106, rs3810936, rs7865494) (Pc = 0.012, OR = 1.662, 95% CI = 1.168-2.363) in patients with scleritis as compared with healthy volunteers. CONCLUSIONS: This study reveals that a TGT haplotype in TNFAIP3 may be a protective factor for the development of scleritis and that a GT haplotype in TNFSF4 and a CCC haplotype in TNFSF15 may be risk factors for scleritis in Chinese Han.

Innate Immune Response and Outcome of Clostridium difficile Infection Are Dependent on Fecal Bacterial Composition in the Aged Host.

Background: Clostridium difficile infection (CDI) is a serious threat for an aging population. Using an aged mouse model, we evaluated the effect of age and the roles of innate immunity and intestinal microbiota. Methods: Aged (18 months) and young (8 weeks) mice were infected with C difficile, and disease severity, immune response, and intestinal microbiome were compared. The same experiment was repeated with intestinal microbiota exchange between aged and young mice before infection. Results: Higher mortality was observed in aged mice with weaker neutrophilic mobilization in blood and intestinal tissue and depressed proinflammatory cytokines in early infection. Microbiota exchange improved survival and early immune response in aged mice. Microbiome analysis revealed that aged mice have significant deficiencies in Bacteroidetes phylum and, specifically, Bacteroides, Alistipes, and rc4-4 genera, which were replenished by cage switching. Conclusions: Microbiota-dependent alteration in innate immune response early on during infection may explain poor outcome in aged host with CDI.

Detecting branching rate heterogeneity in multifurcating trees with applications in lineage tracing data.

Understanding cellular birth rate differences is crucial for predicting cancer progression and interpreting tumor-derived genetic data. Lineage tracing experiments enable detailed reconstruction of cellular genealogies, offering new opportunities to measure branching rate heterogeneity. However, the lineage tracing process can introduce complex tree features that complicate this effort. Here, we examine tree characteristics in lineage tracing-derived genealogies and find that editing window placement leads to multifurcations at a tree's root or tips. We propose several ways in which existing tree topology-based metrics can be extended to test for rate heterogeneity on trees even in the presence of lineage-tracing associated distortions. Although these methods vary in power and robustness, a test based on the J 1 statistic effectively detects branching rate heterogeneity in simulated lineage tracing data. Tests based on other common statistics ( s ^ and the Sackin index) show interior performance to J 1 . We apply our validated methods to xenograft experimental data and find widespread rate heterogeneity across multiple study systems. Our results demonstrate the potential of tree topology statistics in analyzing lineage tracing data, and highlight the challenges associated with adapting phylogenetic methods to these systems.

Light-driven soft microrobots based on hydrogels and LCEs: development and prospects.

In the daily life of mankind, microrobots can respond to stimulations received and perform different functions, which can be used to complete repetitive or dangerous tasks. Magnetic driving works well in robots that are tens or hundreds of microns in size, but there are big challenges in driving microrobots that are just a few microns in size. Therefore, it is impossible to guarantee the precise drive of microrobots to perform tasks. Acoustic driven micro-nano robot can achieve non-invasive and on-demand movement, and the drive has good biological compatibility, but the drive mode has low resolution and requires expensive experimental equipment. Light-driven robots move by converting light energy into other forms of energy. Light is a renewable, powerful energy source that can be used to transmit energy. Due to the gradual maturity of beam modulation and optical microscope technology, the application of light-driven microrobots has gradually become widespread. Light as a kind of electromagnetic wave, we can change the energy of light by controlling the wavelength and intensity of light. Therefore, the light-driven robot has the advantages of programmable, wireless, high resolution and accurate spatio-temporal control. According to the types of robots, light-driven robots are subdivided into three categories, namely light-driven soft microrobots, photochemical microrobots and 3D printed hard polymer microrobots. In this paper, the driving materials, driving mechanisms and application scenarios of light-driven soft microrobots are reviewed, and their advantages and limitations are discussed. Finally, we prospected the field, pointed out the challenges faced by light-driven soft micro robots and proposed corresponding solutions.

Accounting for 16S rRNA copy number prediction uncertainty and its implications in bacterial diversity analyses.

16S rRNA gene copy number (16S GCN) varies among bacterial species and this variation introduces potential biases to microbial diversity analyses using 16S rRNA read counts. To correct the biases, methods have been developed to predict 16S GCN. A recent study suggests that the prediction uncertainty can be so great that copy number correction is not justified in practice. Here we develop RasperGade16S, a novel method and software to better model and capture the inherent uncertainty in 16S GCN prediction. RasperGade16S implements a maximum likelihood framework of pulsed evolution model and explicitly accounts for intraspecific GCN variation and heterogeneous GCN evolution rates among species. Using cross-validation, we show that our method provides robust confidence estimates for the GCN predictions and outperforms other methods in both precision and recall. We have predicted GCN for 592605 OTUs in the SILVA database and tested 113842 bacterial communities that represent an exhaustive and diverse list of engineered and natural environments. We found that the prediction uncertainty is small enough for 99% of the communities that 16S GCN correction should improve their compositional and functional profiles estimated using 16S rRNA reads. On the other hand, we found that GCN variation has limited impacts on beta-diversity analyses such as PCoA, NMDS, PERMANOVA and random-forest test.

A Bionic Venus Flytrap Soft Microrobot Driven by Multiphysics for Intelligent Transportation.

With the continuous integration of material science and bionic technology, as well as increasing requirements for the operation of robots in complex environments, researchers continue to develop bionic intelligent microrobots, the development of which will cause a great revolution in daily life and productivity. In this study, we propose a bionic flower based on the PNIPAM-PEGDA bilayer structure. PNIPAM is temperature-responsive and solvent-responsive, thus acting as an active layer, while PEGDA does not change significantly in response to a change in temperature and solvent, thus acting as a rigid layer. The bilayer flower is closed in cold water and gradually opens under laser illumination. In addition, the flower gradually opens after injecting ethanol into the water. When the volume of ethanol exceeds the volume of water, the flower opens completely. In addition, we propose a bionic Venus flytrap soft microrobot with a bilayer structure. The robot is temperature-responsive and can reversibly transform from a 2D sheet to a 3D tubular structure. It is normally in a closed state in both cold (T < 32 °C) and hot water (T > 32 °C), and can be used to load and transport objects to the target position (magnetic field strength < 1 T).

Microbial genomic trait evolution is dominated by frequent and rare pulsed evolution.

On the macroevolutionary time scale, does trait evolution proceed gradually or by rapid bursts (pulses) separated by prolonged periods of stasis or slow evolution? Although studies have shown that pulsed evolution is prevalent in animals, our knowledge about the tempo and mode of evolution across the tree of life is very limited. This long-standing debate calls for a test in bacteria and archaea, the most ancient and diverse forms of life with unique population genetic properties. Using a likelihood-based framework, we show that pulsed evolution is not only present but also prevalent and predominant in microbial genomic trait evolution. We detected two distinct types of pulsed evolution (small frequent and large rare jumps) that are predicted by the punctuated equilibrium and quantum evolution theories. Our findings suggest that major bacterial lineages could have originated in quick bursts and that pulsed evolution is a common theme across the tree of life.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Apple cider vinegar soaks do not alter the skin bacterial microbiome in atopic dermatitis.

INTRODUCTION: Atopic dermatitis is a common skin disease characterized by altered cutaneous immunity in which patients often exhibit lower skin microbiota diversity compared to healthy skin and are prone to colonization by Staphylococcus aureus. Apple cider vinegar has been shown to have antibacterial effects; however, its effects on the skin microbiome have not previously been well-described. OBJECTIVES: We aimed to examine the effects of topical dilute apple cider vinegar soaks on Staphylococcus aureus abundance, skin bacterial microbiome composition, and skin bacterial microbiome diversity in atopic dermatitis participants compared to healthy skin. METHODS: Eleven subjects with atopic dermatitis and 11 healthy controls were enrolled in this randomized, non-blinded, single-institution, split-arm pilot study. Subjects soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other forearm in tap water for 10 minutes daily. Skin bacteria samples were collected from subjects' volar forearms before and after 14 days of treatment. 16S sequencing was used to analyze Staphylococcus aureus abundance and skin bacterial microbiome composition, and alpha diversity of microbiota were determined using Shannon diversity index. RESULTS: There was no difference in skin bacterial microbiome in atopic dermatitis subjects after 2 weeks of daily water or apple cider vinegar treatments (p = 0.056 and p = 0.22, respectively), or in mean abundance of S. aureus on apple cider vinegar-treated forearms (p = 0.60). At 2 weeks, the skin bacterial microbiomes of healthy control subjects were not significantly different from the skin bacterial microbiome of atopic dermatitis subjects (p = 0.14, 0.21, 0.12, and 0.05). CONCLUSIONS: Our results suggest that daily soaks in 0.5% apple cider vinegar are not an effective method of altering the skin bacterial microbiome in atopic dermatitis. Further studies are needed to explore the effects of different concentrations of apple cider vinegar on skin microflora and disease severity. TRIAL NUMBER: UVA IRB-HSR #19906.

Tuberculosis Exposure With Risk of Behçet Disease Among Patients With Uveitis.

IMPORTANCE: Although experimental studies support the hypothesis that exposure of infectious agents may trigger an aberrant immune response and contribute to noninfectious uveitis, the association of a definite pathogen with human noninfectious uveitis conditions appears not to have been well established in a population. OBJECTIVE: To evaluate associations of tuberculosis infection with risk of several noninfectious uveitis conditions. DESIGN, SETTING, AND PARTICIPANTS: These mendelian randomization and observational analyses were conducted with the genetic data of a Chinese cohort enrolled between April 2008 and January 2018 and a Japanese cohort enrolled between January 2002 and June 2009. We recruited participants for T-SPOT.TB (Oxford Immunotec) assays between July and November 2019. The Chinese cohort included patients with uveitis associated with Behçet disease or other uveitis conditions and control participants. The Japanese cohort and the group given T-SPOT.TB assays included individuals with Behçet disease and control participants. Data analyses for this study were completed from July 2019 to January 2020. EXPOSURES: Genetic variants associated with tuberculosis as natural proxies for tuberculosis exposure. MAIN OUTCOMES AND MEASURES: The primary outcome was the odds ratio (OR) for Behçet disease, estimated by an inverse variance weighted mean of associations with genetically determined tuberculosis susceptibility. The T-SPOT.TB positivity rate was examined in individuals with Behçet disease and compared with that of control participants. RESULTS: The Chinese cohort included 999 patients with uveitis associated with Behçet disease, 1585 with other uveitis conditions, and 4417 control participants. The Japanese cohort included 611 individuals with Behçet disease and 737 control participants. The group given T-SPOT.TB assays included 116 individuals with Behçet disease and 121 control participants. Of the Chinese individuals with Behçet disease and control participants, 2257 (41.7%) were female and the mean (SD) age was 35.4 (12.5) years. In the Japanese cohort, 564 (41.8%) were female and the mean (SD) age was 39.1 (12.7) years. Genetically determined tuberculosis susceptibility was associated with an increased risk for Behçet disease. The OR for Behçet disease per 2-fold increase in tuberculosis incidence was 1.26 (95% CI, 1.12-1.43; P = 1.47 × 10-4). Replication using the Japanese cohort yielded similar results (OR, 1.16 [95% CI, 1.08-1.26]). In T-SPOT.TB assays, having a positive result, indicating a history of tuberculosis infection, was found to be an independent risk factor for Behçet disease (OR, 2.26 [95% CI, 1.11-4.60]). CONCLUSIONS AND RELEVANCE: These human genetic and biomarker data demonstrated that tuberculosis exposure was a risk factor for Behçet disease. This study provides novel evidence linking an infectious agent to the risk of a noninfectious uveitis condition.

Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding.

The widespread availability of energy-dense, rewarding foods is correlated with the increased incidence of obesity across the globe. Overeating during mealtimes and unscheduled snacking disrupts timed metabolic processes, which further contribute to weight gain. The neuronal mechanism by which the consumption of energy-dense food restructures the timing of feeding is poorly understood. Here, we demonstrate that dopaminergic signaling within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, disrupts the timing of feeding, resulting in overconsumption of food. D1 dopamine receptor (Drd1)-null mice are resistant to diet-induced obesity, metabolic disease, and circadian disruption associated with energy-dense diets. Conversely, genetic rescue of Drd1 expression within the SCN restores diet-induced overconsumption, weight gain, and obesogenic symptoms. Access to rewarding food increases SCN dopamine turnover, and elevated Drd1-signaling decreases SCN neuronal activity, which we posit disinhibits downstream orexigenic responses. These findings define a connection between the reward and circadian pathways in the regulation of pathological calorie consumption.

Comparison of end-of-life tire treatment technologies: a Chinese case study.

The aim of this paper is to compare different end-of-life tire (ELT) treatment technologies in China from an environmental and economic perspective. Four treatment technologies were evaluated: ambient grinding, devulcanization, pyrolysis and illegal tire oil extraction. Life cycle assessment (LCA) was applied to evaluate the potential environmental impact of each treatment based on the Eco-indicator 99 (Hierarchist approach) method provided by GaBi 4 software. The final result shows that pyrolysis represents the environmentally benign option while illegal tire oil extraction caused the worst damages. For the three legal treatments, although high credit was obtained when considering avoided impacts from recycled materials and energy, they have great impact as to respiratory effects (inorganic) dominantly contributed by energy production stage, which implies that the emphasis on environmental policies related to ELT treatment should shift from the control of emissions from treatment process to the reduction of energy consumption. A simplified comparison of net benefits and total impacts shows that the most eco-effective ELT treatment technology is pyrolysis, followed by dynamic devulcanization and ambient grinding. The illegal tire oil extraction, however, must be prohibited immediately because of its highest environmental pollution and lowest net benefit.