Deterministic evolution and stringent selection during preneoplasia.

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory.

BACKGROUND & AIMS: Hepatocellular Carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma (AHCC) trials group (NCT03267641), we recruited one of the largest prospective cohorts of HCC with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provided a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort) IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected HCC, reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of Hepatocellular Carcinoma (HCC). These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for developing personalized therapies tailored to specific tumor evolutionary and transcriptomic profiles. The co-existence of multiple sub-types within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making.

Nano-Confined Effect and Heterojunction Promoted Exciton Separation for Light-Boosted Osmotic Energy Conversion.

The osmotic energy conversion properties of biomimetic light-stimulated nanochannels have aroused great interest. However, the power output performance is limited by the low light-induced current and energy conversion efficiency. Here, nanochannel arrays with simultaneous modification of ZnO and di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,20-bipyridyl-4,40-dicarboxylato) ruthenium (II) (N719) onto anodic aluminum oxide (AAO) to combine the nano-confined effect and heterojunction is designed, which demonstrate rectified ion transport behavior due to the asymmetric composition, structure and charge. High cation selectivity and ion flux contribute to the high power density of ≈7.33 W m-2 by mixing artificial seawater and river water. Under light irradiation, heterojunction promoted the production and separation of exciton, enhanced cation selectivity, and improved the utilization efficiency of osmotic energy, providing a remarkable power density of ≈18.49 W m-2 with an increase of 252% and total energy conversion efficiency of 30.43%. The work opens new insights into the biomimetic nanochannels for high-performance energy conversion.

Room-Temperature Synthesis of a COFs Membrane Via LBL Self-Assembly Strategy for Energy Harvesting.

The covalent organic frameworks (COFs) membrane with ordered and confined one-dimensional channel has been considered as a promising material to harvest the salinity gradient energy from the seawater and river water. However, the application of the COFs in the field of energy conversion still faces the challenges in membrane preparation. Herein, energy harvesting is achieved by taking advantage of a COFs membrane where TpDB-HPAN is synthesized via layer-by-layer self-assembly strategy at room temperature. The carboxy-rich TpDB COFs can be expediently assembled onto the substrate with an environmental-friendly method. The increased open-circuit voltage (Voc ) endows TpDB-HPAN membrane with a remarkable energy harvesting performance. More importantly, the application perspective is also illuminated by the cascade system. With the advantages of green synthesis, the TpDB-HPAN membrane can be considered as a low-cost and promising candidate for energy conversion.

Large-Area Covalent Organic Polymers Membrane via Sol-Gel Approach for Harvesting the Salinity Gradient Energy.

Many materials with nanofluidic channels are exploited to achieve salinity gradient energy conversion. However, most materials are fragile, difficult to process, or only prepared into a limited size, which greatly restricts their practical application in the future. Herein, a covalent organic polymers membrane with high mechanical property and stability is fabricated, which can keep integrity in harsh conditions for up to 1 month. In addition, by using the sol-gel approach, a large-area membrane with an area of 26 × 26 cm is expediently fabricated in lab conditions. When the membrane is applied to salinity gradient energy conversion, the maximum output power density is up to 6.21 W m-2 . This work provides a simple method for the fabrication of large-area membrane for salinity gradient energy conversion in future real-world applications.

Brain Wave-Like Signal Modulator by Ionic Nanochannel Rectifier Bridges.

Smart modulation of bioelectric signals is of great significance for the development of brain-computer interfaces, bio-computers, and other technologies. The regulation and transmission of bioelectrical signals are realized through the synergistic action of various ion channels in organisms. The bionic nanochannels, which have similar physiological working environment and ion rectification as their biological counterparts, can be used to construct ion rectifier bridges to modulate the bioelectric signals. Here, the artificial smart ionic rectifier bridge with light response is constructed by anodic aluminum oxide (AAO)/poly (spiropyran acrylate) (PSP) nanochannels. The output ion current of the rectifier bridge can be switched between "ON" and "OFF" states by irradiation with UV and visible (Vis) light, and the conversion efficiency (η) of the system in "ON" state is ≈70.5%. The controllable modulation of brain wave-like signal can be realized by ionic rectifier bridge. The ion transport properties and processes of ion rectifier bridges are explained using theoretical calculations based on Poisson-Nernst-Planck (PNP) equations. These findings have significant implications for the understanding of the intelligent ionic circuit and combination of artificial smart ionic channels to organisms, which provide new avenues for development of intelligent ion devices.

PSiTE: a Phylogeny guided Simulator for Tumor Evolution.

SUMMARY: Simulating realistic clonal dynamics of tumors is an important topic in cancer genomics. Here, we present Phylogeny guided Simulator for Tumor Evolution, a tool that can simulate different types of tumor samples including single sector, multi-sector bulk tumor as well as single-cell tumor data under a wide range of evolutionary trajectories. Phylogeny guided Simulator for Tumor Evolution provides an efficient tool for understanding clonal evolution of cancer. AVAILABILITY AND IMPLEMENTATION: PSiTE is implemented in Python and is available at https://github.com/hchyang/PSiTE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Confinement Effect of Angstrom-Sized Pores in Asymmetrical Membrane Constructed by Zeolitic Imidazolate Frameworks: Partially Dehydrated Ion Transport Performance.

The confinement effect in asymmetrical biological ion channels makes the state of molecules and ions differs from that in the external environment, and the mass transfer confined in the biological ion channels is in a single strand form. Herein, an asymmetrical membrane with angstrom-sized pores is constructed by growth of ZIF-90 membrane on the porous anodic aluminum oxide film. Due to the confinement effect of angstrom-sized pores of ZIF-90, ions transport through the pores of ZIF-90 suffer from multiple dehydration-hydration-dehydration process in the form of a single ionic chain. Molecular dynamics simulations imply that ions inside the pores of ZIF-90 are partially dehydrated. In alkaline condition, high rectification ratios of 237, 295, and 357 can be achieved in 10 × 10-3 m KCl, NaCl, and LiCl electrolyte, respectively. Besides, the strong electrostatic interaction between ions and the confined ZIF-90 pores makes the ions transport through the asymmetrical membrane suffer from an energy barrier, and the energy barrier is different with different ion species. This work helps to understand the ions transfer mechanism through angstrom-sized pores, which can provide guidance for the design of asymmetrical membrane and boost their applications.

Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice.

BACKGROUND: The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. METHODS: Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. RESULTS: Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-ß/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. CONCLUSIONS: These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.

Rod-Cell-Mimetic Photochromic Layered Ion Channels with Multiple Switchable States for Controllable Ion Transport.

The controllable ion transport in the photoreceptors of rod cells is essentially important for the light detection and information transduction in visual systems. Herein, inspired by the photochromism-regulated ion transport in rod cells with stacking structure, layered ion channels have been developed with a visual photochromic function induced by the alternate irradiation with visible and UV light. The layered structure is formed by stacking spiropyran-modified montmorillonite 2D nanosheets on the surface of an alumina nanoporous membrane. The visual photochromism resulting from the photoisomerization of spiropyran chromophores reversibly regulates the ion transport through layered ion channels. Furthermore, the cooperation of photochromism and pH value achieves multiple switchable states of layered ion channels for the controllable ion transport mimicking the biological process of the visual cycle. The ion transport properties of these states are explained quantitatively by a theoretical calculation based on the Poisson and Nernst-Plank (PNP) equations.

A program to compute the soft Robinson-Foulds distance between phylogenetic networks.

BACKGROUND: Over the past two decades, phylogenetic networks have been studied to model reticulate evolutionary events. The relationships among phylogenetic networks, phylogenetic trees and clusters serve as the basis for reconstruction and comparison of phylogenetic networks. To understand these relationships, two problems are raised: the tree containment problem, which asks whether a phylogenetic tree is displayed in a phylogenetic network, and the cluster containment problem, which asks whether a cluster is represented at a node in a phylogenetic network. Both the problems are NP-complete. RESULTS: A fast exponential-time algorithm for the cluster containment problem on arbitrary networks is developed and implemented in C. The resulting program is further extended into a computer program for fast computation of the Soft Robinson-Foulds distance between phylogenetic networks. CONCLUSIONS: Two computer programs are developed for facilitating reconstruction and validation of phylogenetic network models in evolutionary and comparative genomics. Our simulation tests indicated that they are fast enough for use in practice. Additionally, the distribution of the Soft Robinson-Foulds distance between phylogenetic networks is demonstrated to be unlikely normal by our simulation data.

A program for verification of phylogenetic network models.

MOTIVATION: Genetic material is transferred in a non-reproductive manner across species more frequently than commonly thought, particularly in the bacteria kingdom. On one hand, extant genomes are thus more properly considered as a fusion product of both reproductive and non-reproductive genetic transfers. This has motivated researchers to adopt phylogenetic networks to study genome evolution. On the other hand, a gene's evolution is usually tree-like and has been studied for over half a century. Accordingly, the relationships between phylogenetic trees and networks are the basis for the reconstruction and verification of phylogenetic networks. One important problem in verifying a network model is determining whether or not certain existing phylogenetic trees are displayed in a phylogenetic network. This problem is formally called the tree containment problem. It is NP-complete even for binary phylogenetic networks. RESULTS: We design an exponential time but efficient method for determining whether or not a phylogenetic tree is displayed in an arbitrary phylogenetic network. It is developed on the basis of the so-called reticulation-visible property of phylogenetic networks. AVAILABILITY AND IMPLEMENTATION: A C-program is available for download on http://www.math.nus.edu.sg/∼matzlx/tcp_package CONTACT: matzlx@nus.edu.sg SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Clinicopathological and prognostic significance of survivin expression in renal cancer patients: a meta-analysis.

BACKGROUND: Survivin has been reported to play a role in the diagnosis and prognosis of renal cell carcinoma (RCC); however, published data on this subject are conflicting. AIM: To conduct a meta-analysis to evaluate the impact of survivin as a prognostic marker and its association with clinicopathological variables in patients with RCC. METHOD: Comprehensive searches of electronic databases (PubMed, ISI Web of Knowledge Embase, Google Scholar Web and the Cochrane Library) were updated to June 2016 to retrieve eligible studies. The association strength was measured with relative risks (RRs) and pooled HRs with 95% CIs, which were extracted and pooled to determine the association between survivin expression and patient survival and clinicopathological features. RESULTS: Ten studies with 1063 cases of RCC were included. Positive survivin expression in RCC was associated with the TNM stage (pooled RR 1.49; 95% CI 1.07 to 2.07) or Fuhrman grade (pooled RR 1.63; 95% CI 1.15 to 2.32) in patients. The correlation between survivin expression and gender was not significant (pooled RR 0.97; 95% CI 0.83 to 1.15). In addition, a considerable association was found between survivin expression and overall survival for patients with RCC (pooled HR 1.94; 95% CI 1.24 to 3.05 (multivariate model) and 5.41; 95% CI 4.08 to 7.17 (univariate model)). CONCLUSIONS: Our results indicate that survivin is of prognostic significance in patients with RCC.

Down-regulation of Sphk2 suppresses bladder cancer progression.

Bladder cancer is the second most common urological malignancy around the world and is by far the most frequent urological malignancy in China. The abnormal expression of sphingosine kinase 2 (SphK2) is associated with tumor progression and a poor patient survival rate, however, the effect of SphK2 on the bladder cancer cells remains unclear. The aim of the paper was to study the expression of SphK2 in bladder cancer and the role of SphK2 on the cell proliferation, metastasis, and apoptosis in bladder cancer in vitro. Our results showed that SphK2 is up-regulated in bladder cancer tissues compared with the corresponding adjacent non-neoplastic tissues, and the expression level of SphK2 was significantly higher in human bladder cancer cells in comparison with normal bladder epithelial cells. Silencing of SphK2 could inhibit the proliferation ability of T24 cells in vitro. In addition, SphK2 knockdown could induce a significant increase in the number of apoptotic cells. Furthermore, the transwell assay also showed significant cell migration inhibition in SphK2 siRNA transfectant compared with cell lines transfected with NC. Thus, this study suggested that SphK2 inhibition may provide a promising treatment for bladder cancer patients.

High-performance osmotic energy harvesting enabled by the synergism of space and surface charge in two-dimensional nanofluidic membranes.

As promising prospects for renewable power harvesting, two-dimensional (2D) nanochannels for osmotic energy capture in a reverse electrodialysis arrangement have garnered significant attention. However, existing 2D nanochannel membranes have shown limited power generation capabilities due to challenges in balancing ion flux and selectivity. Here, we construct montmorillonite (MMT)/TEMPO-mediated oxidation cellulose nanofibers (TOCNFs) nanocomposite membranes for enhanced ion transmembrane transport. The intercalation of TOCNFs not only enlarges the interlayer distance, but also provides abundant space charge inside the nanochannels. Benefiting from the strong ion selectivity and high ion flux, the composite membrane achieves a remarkable power output of ∼16.57 W/m2 in the gradient of artificial seawater and river water, exceeding that of the state-of-the-art heterogeneous membrane-based osmotic energy conversion systems. Both experimental and theoretical findings confirm that the synergism of space and surface charge plays a crucial role in promoting osmotic energy conversion. This research contributes valuable insights into the optimization of 2D membranes for efficient clean energy harvesting purposes.

Accelerated biological aging mediated associations of ammonium, sulfate in fine particulate matter with liver cirrhosis.

BACKGROUND: Although both air pollution and aging are related to the development of liver cirrhosis, the role of biological aging in association of the mixture of fine particulate matter (PM2.5) and its constituents with liver cirrhosis was unknown. METHODS: This case-control retrospective study included 100 liver cirrhosis patients and 100 control subjects matched by age and sex. The concentrations of PM2.5 and its constituents were estimated for patients using machine-learning methods. The clinical biomarkers were used to calculate biological age using the Klemera-Doubalmethod (KDM) algorithms. Individual associations of PM2.5 and its constituents or biological age with liver cirrhosis were analyzed by generalized linear models. WQS and BKMR were applied to analyze association of mixture of PM2.5 and its constituents with liver cirrhosis. The mediation effect of biological age on associations of PM2.5 and its constituents with liver cirrhosis was further explored. RESULTS: we found that each 1-unit increment in NH4+, NO3-, SO42- and biological age were related to 3.618-fold (95%CI: 1.896, 6.904), 1.880-fold (95%CI: 1.319, 2.680), 2.955-fold (95%CI: 1.656, 5.272) and 1.244-fold (95%CI: 1.093, 1.414) increased liver cirrhosis. Both WQS and BKMR models showed that the mixture of PM2.5 and its constituents was related to increased liver cirrhosis. Furthermore, the mediated proportion of biological age on associations of NH4+ and SO42- with liver cirrhosis were 14.7 % and 14.6 %, respectively. CONCLUSIONS: Biological aging may partly explain the exposure to PM2.5 and its constituents in association with increased risk for liver cirrhosis, implying that delaying the aging process may be a key step for preventing PM2.5-related liver cirrhosis risk.

Comprehensively identifying and characterizing the missing gene sequences in human reference genome with integrated analytic approaches.

The human reference genome is still incomplete and a number of gene sequences are missing from it. The approaches to uncover them, the reasons causing their absence and their functions are less explored. Here, we comprehensively identified and characterized the missing genes of human reference genome with RNA-Seq data from 16 different human tissues. By using a combined approach of genome-guided transcriptome reconstruction coupled with genome-wide comparison, we uncovered 3.78 and 2.37 Mb transcribed regions in the human genome assemblies of Celera and HuRef either missed from their homologous chromosomes of NCBI human reference genome build 37.2 or partially or entirely absent from the reference. We further identified a significant number of novel transcript contigs in each tissue from de novo transcriptome assembly that are unalignable to NCBI build 37.2 but can be aligned to at least one of the genomes from Celera, HuRef, chimpanzee, macaca or mouse. Our analyses indicate that the missing genes could result from genome misassembly, transposition, copy number variation, translocation and other structural variations. Moreover, our results further suggest that a large portion of these missing genes are conserved between human and other mammals, implying their important biological functions. Totally, 1,233 functional protein domains were detected in these missing genes. Collectively, our study not only provides approaches for uncovering the missing genes of a genome, but also proposes the potential reasons causing genes missed from the genome and highlights the importance of uncovering the missing genes of incomplete genomes.

CNETML: maximum likelihood inference of phylogeny from copy number profiles of multiple samples.

Phylogenetic trees based on copy number profiles from multiple samples of a patient are helpful to understand cancer evolution. Here, we develop a new maximum likelihood method, CNETML, to infer phylogenies from such data. CNETML is the first program to jointly infer the tree topology, node ages, and mutation rates from total copy numbers of longitudinal samples. Our extensive simulations suggest CNETML performs well on copy numbers relative to ploidy and under slight violation of model assumptions. The application of CNETML to real data generates results consistent with previous discoveries and provides novel early copy number events for further investigation.

Single and binary adsorption of lead and cadmium ions in aqueous solutions and river water by butylamine functionalized vermiculite: performance and mechanism.

Lead and cadmium are toxic to human, animal, and plant health; they enhance oxidative stress indirectly while simultaneously acting through other toxicodynamic mechanisms. In this study, pristine vermiculite (VER) was functionalized with butylamine (BUT) and a novel organoclay (BUT-VER) adsorbent material was produced for simultaneous removal of Pb(II) and Cd(II) in aquatic medium. The adsorbents were characterized by spectroscopic, microscopic, spectrometric, and potentiometric techniques. The adsorption affecting parameters, including pH, time, initial concentration, temperature, and co-existing cations were investigated and optimized. The kinetic data results were in better agreement with pseudo-second-order (PSO) model (R2 > 0.992). Multiple isotherm models were used to study the adsorption system and results showed that adsorption was monolayer. The BUT-VER showed an improvement in adsorption capacity in a single system (Pb(II): from 134.2 to 160.6 mg g-1) and (Cd(II): from 51.1 to 58.9 mg g-1) while in binary system (Pb(II): from 107.3 to 114.5 mg g-1) and (Cd(II): from 33.7 to 39.7 mg g-1), respectively. Furthermore, BUT-VER was tested in real river water and removed efficiency of >99% was achieved in just 1 h. The dominant mechanisms were electrostatic attraction and complexation. BUT-VER was regenerated for five consecutive cycles and showed >90% removal efficiency. These findings suggest that the proposed inexpensive adsorbent has the potential for practical applications of toxic metals removal from water.

The nonstructural protein NSs encoded by tomato zonate spot virus suppresses RNA silencing by interacting with NbSGS3.

Viral suppressors of RNA silencing (VSRs) are encoded by diverse viruses to counteract the RNA silencing-mediated defence mounted by the virus-infected host cells. In this study, we identified the NSs protein encoded by tomato zonate spot virus (TZSV) as a potent VSR, and used a potato virus X (PVX)-based heterologous expression system to demonstrate TZSV NSs as a viral pathogenicity factor that intensified PVX symptoms in Nicotiana benthamiana. We then used a yeast two-hybrid screen to identify the suppressor of gene silencing 3 protein of N. benthamiana (NbSGS3), a known component of the plant RNA silencing pathway, as an interaction partner of TZSV NSs. We verified this interaction in plant cells with bimolecular fluorescence complementation, subcellular colocalization, and co-immunoprecipitation. We further revealed that the NSs-NbSGS3 interaction correlated with the VSR activity of TZSV NSs. TZSV NSs reduced the concentration of NbSGS3 protein in plant cells, probably through the ubiquitination and autophagy pathways. Interestingly, TZSV infection, but not NSs overexpression, significantly up-regulated the NbSGS3 transcript levels. Our data indicate that TZSV NSs suppresses RNA silencing of the host plant and enhances TZSV pathogenicity through its interaction with NbSGS3. This study reveals a novel molecular mechanism of NSs-mediated suppression of plant host antiviral defence.