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Cardiac fibrosis is a process characterized by extracellular matrix accumulation leading to myocardial dysfunction. Angiotensin II (Ang II) has been shown to play an important role in the pathogenesis of cardiac fibrosis. However, the underlying mechanisms are not well established. Dysfunction of adipose tissue has been shown to promote remote organ injury, but its role in Ang II-induced cardiac remodeling is still unclear. In this study, we demonstrated that epididymal white adipose tissue (eWAT) promoted Ang II-induced cardiac fibrosis and subsequent cardiac dysfunction in an exosome-dependent manner. Both eWAT removal and administration of an inhibitor of exosome biogenesis strongly attenuated Ang II-induced abnormalities. Moreover, exosomes isolated from Ang II-stimulated adipocytes promoted cardiac fibroblasts (CFs) activity. A mechanistic study identified that the miR-23a-3p level was significantly increased in exosomes derived from Ang II-challenged adipocytes and serum exosomes from Ang II-infused mice. Importantly, tail vein injection of ago-miR-23a-3p caused cardiac fibrosis and dysfunction, while antago-miR-23a-3p inhibited Ang II-induced cardiac fibrosis. Bioinformatics analysis and further validation experiments revealed that RAP1 is a direct downstream target of miR-23a-3p, and overexpression of RAP1 reversed the profibrotic effect of miR-23a-3p. Taken together, these findings elucidated the role of eWAT in Ang II-induced myocardial fibrosis and indicated that adipocyte-derived exosomes mediate pathologic communication between dysfunctional adipose tissue and the heart by transporting miR-23a-3p into CFs, transforming fibroblasts into myofibroblasts and promoting excessive collagen deposition by targeting RAP1. Prevention of abnormal adipocyte exosome production, inhibition of miR-23a-3p biogenesis, and treatment with a miR-23a-3p antagonist are novel strategies for treating cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Significant gaps remain in understanding of gas-melt interfaces in foamed glass systems. We attempt to address these gaps by reporting on the transition of local structure, ionic (molecular) diffusion, and melt viscosity of CaCO 3 -foamed soda-lime-silica glass using molecular dynamics calculations and experimental analyses. Our calculations show that despite the continual increase in network modifying CaO, the melt network experiences an abnormal polymerization process in the initial stage because of Na ion penetration from the melt skeleton to the interface. The percolation probability decays from the surface to the center of melt because of the gradual polymerized network structure, boosting nonmonotonic changes in the [SiO 4 ] species, equilibrium constants, and average residual charge per O atom. Furthermore, the diffusion capacities of melt ions and CO 2 molecules peak at 6 wt% CaCO 3 addition, attributed to the combined effects of melt depolymerization and interface constraint. The viscosity jump occurring at 1 wt% CaCO 3 addition results in the optimal sample with an even cellular glass framework and strong matrix. These findings contribute to the precise control of foamed glass with optimal performance. • Gas-melt interfaces in the foamed glass systems are constructed by MD simulations. • Simulations reveal short-range interaction differences between melt basic cations and CO 2 molecules. • An anomalous sub-diffusion regime is attributed to the restriction of gas-liquid interface on diffusion behavior. • A viscosity jump is produced due to the enrichment of network modifiers at the interface. • The viscosity jump boosts the formation of an even cellular glass framework. [ABSTRACT FROM AUTHOR]

• M2 macrophages drive pulmonary fibrosis progression. • Icariside II attenuates IL-4-induced M2 polarization by regulating PI3K/Akt/β-catenin signaling. • Icariside II alleviates fibroblast activation induced by conditioned media from M2 macrophages. • Icariside II attenuates bleomycin-induced fibrosis by regulating M2 macrophages. • Targeting β-catenin with Icariside II offers a potential IPF therapeutic approach. Idiopathic pulmonary fibrosis (IPF) is a debilitating interstitial lung disorder characterized by its limited therapeutic interventions. Macrophages, particularly the alternatively activated macrophages (M2 subtype), have been acknowledged for their substantial involvement in the development of pulmonary fibrosis. Hence, targeting macrophages emerges as a plausible therapeutic avenue for IPF. Icariside II (ISE II) is a natural flavonoid glycoside molecule known for its excellent anti-tumor and anti-fibrotic activities. Nevertheless, the impact of ISE II on pulmonary fibrosis and the intricate mechanisms through which it operates have yet to be elucidated. To scrutinize the impact of ISE II on the regulation of M2 macrophage polarization and its inhibitory effect on pulmonary fibrosis, as well as to delve deeper into the underlying mechanisms of its actions. The effect of ISE II on proliferation and apoptosis in RAW264.7 cells was assessed through the use of EdU-488 labeling and the Annexin V/PI assay. Flow cytometry, western blot, and qPCR were employed to detect markers associated with the M2 polarization phenotype. The anti-fibrotic effects of ISE II in NIH-3T3 cells were investigated in a co-culture with M2 macrophages. Si-Ctnnb1 and pcDNA3.1(+)-Ctnnb1 plasmid were used to investigate the mechanism of targeted intervention. The murine model of pulmonary fibrosis was induced by intratracheal administration of bleomycin (BLM). Pulmonary function, histopathological manifestations, lung M2 macrophage infiltration, and markers associated with pulmonary fibrosis were evaluated. Furthermore, in vivo transcriptomics analysis was employed to elucidate differentially regulated genes in lung tissues. Immunofluorescence, western blot, and immunohistochemistry were conducted for corresponding validation. Our investigation demonstrated that ISE II effectively inhibited the proliferation of RAW264.7 cells and mitigated the pro-fibrotic characteristics of M2 macrophages, exemplified by the downregulation of CD206, Arg-1, and YM-1, Fizz1, through the inhibition of the PI3K/Akt/β-catenin signaling pathway. This impact led to the amelioration of myofibroblast activation and the suppression of nuclear translocation of β-catenin of NIH-3T3 cells in a co-culture. Consequently, it resulted in decreased collagen deposition, reduced infiltration of profibrotic macrophages, and a concurrent restoration of pulmonary function in mice IPF models. Furthermore, our RNA sequencing results showed that ISE II could suppress the expression of genes related to M2 polarization, primarily by inhibiting the PI3K/Akt and β-catenin signaling pathway. In essence, our findings suggest that ISE II holds potential as an anti-fibrotic agent by orchestrating macrophage polarization. This may have significant implications in clinical practice. This study has provided evidence that ISE II exerts a significant anti-fibrotic effect by inhibiting macrophage M2 polarization through the suppression of the PI3K/Akt/β-catenin signaling pathway. These findings underscore the potential of ISE II as a promising candidate for the development of anti-fibrotic pharmaceuticals in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

Benzodithiophene derivatives represent a category of planar and rigid sulfur-containing heterocyclic molecules that possess a diverse range of applications in the development of organic optoelectronic materials, due to their versatile chemical structures and exceptional optoelectronic properties. Depending on the different connection positions between the benzene ring and thiophene, benzodithiophene can be classified into four constitutional isomers. In particular, benzo [1,2- b :4,5- b' ]dithiophene (BDT) has found extensive utility as fundamental components in various photovoltaic polymers and small molecule materials. This article provides a comprehensive review of the research progress of BDT materials in fields such as organic solar cells, electrochromic devices, organic field-effect transistors, and biomedical imaging, with a specific focus on their performance in organic solar cells. The article explores molecular design strategies, chemical structures, and photovoltaic performance of these materials, providing valuable insights for the design and synthesis of novel BDT-based derivatives with enhanced performance and stability in the future. [Display omitted] • Benzodithiophene: Multifunctional sulfur-containing molecule with excellent optoelectronic properties. • Summary of novel BDT synthesis methods. • Exploring the relationship between molecular design, structure, and properties to guide future BDT derivative synthesis. • Latest applications of BDT materials in organic solar cells, organic field-effect transistors, and biomedical imaging. [ABSTRACT FROM AUTHOR]

• We explore the interaction effect between CEO overconfidence and investor sentiment on merger decision-making. • The influence of CEO overconfidence on merger frequency is stronger during periods of high investor sentiment. • Bullish market trends motivate overconfident CEOs to pursue diversifying mergers, while bearish trends encourage cash payments. • Investor sentiment is a more dominant determinant than CEO overconfidence in shaping merger decisions. This study investigates the interactive impact of CEO overconfidence and investor sentiment on merger behavior in U.S. firms. We find that the influence of CEO overconfidence on merger frequency is stronger during periods of high investor sentiment, diminishing in low sentiment times. It suggests that investor sentiment is a more dominant determinant than CEO overconfidence in shaping merger frequency. Furthermore, a bullish market trend motivates overconfident CEOs to pursue diversifying mergers, while a bearish market trend encourages cash payments. Overall, overconfident CEOs adapt their merger behavior based on the economic environment, with investor sentiment playing a dominant role in decision-making. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) have potential applications in immobilized enzyme fields due to their unique chemical and mechanical properties. First, a novel COF material for immobilizing enzyme for preparing ginsenosides was obtained using 1,3,5-tricarbaldehyde and 3,3′-dihydroxybenzidine （BTDH）as organic monomers. Then the morphology, stability, pore size and the loading capacity of COF-BTDH were investigated using transmission electron microscopy, Fourier transform infrared (FT-IR), and loading capacity experiments. At last effect of reaction time on ginsenoside extraction efficiency and the maximum usage amount of material were explored. Results showed that pectinase was effectively immobilized on COF-BTDH. In addition the optimized reaction time of catalytic hydrolysis for extracting ginsenosides Rb1 and Rd was 2 h, and the mass ratio of material to enzyme was 31.25:1. Additionally, the immobilized enzyme remained more than 85% active according to the amount ratio of ginsenoside Rd after five consecutive cycles. [Display omitted] • A COF material with dihydroxybenzidine (BTDH) as monomer was used for immobilizing pectinase. • The mass ratio of material to enzyme was 31.25:1 for extracting ginsenoside Rb1 and Rd. • The immobilized pectinase remained more than 85% active after five consecutive cycles. [ABSTRACT FROM AUTHOR]

In this study, a novel bilayer Pickering emulsion stabilized by zein modification via selenium nanoparticles (Se NPs) was developed. Under the guidance of morphology and encapsulation efficiency of oil, the synthesis process of the Pickering emulsion was optimized. The formation mechanism of the Pickering emulsion was speculated based on the microstructure, distribution of selenium and competition adsorption at the oil/water interface. Then, the influence of the concentration of zein in the zein-selenium nanoparticles on Pickering emulsion was discussed according to the size of emulsion droplets, freeze-drying stability, rheology and lipid oxidation. Finally, an in vivo experiment was used to investigate the skin penetration and biodistribution of Pickering emulsion containing selenium. The results indicated that zein NPs were adsorbed on the surface of selenium and formed a bilayer Pickering emulsion. Under optimized conditions, the size of the emulsion droplets could remain 11.60 ± 0.13 μm, and no obvious coalescence or instability occurred after 60 days of storage. The increase in zein concentration had a positive effect on the encapsulation efficiency of oil, rheology and oxidation resistance of Pickering emulsion. In addition, this research provided a potential synthesis strategy for the introduction of other inorganic trace elements into Pickering emulsion and further applications. Top: Schematic diagram of the formation of Pickering emulsion and the effect of Zein concentration to the emulsion Down: The rheology, selenium content and permeability in vivo of Pickering emulsion. The photographs were plotted by Hao Wang. [Display omitted] • Pickering emulsions stabilized by Zein-selenium nanoparticles were developed. • Zein could avoid the accumulation of nano-selenium at the oil-water interface. • Pickering emulsions with high content of Zein showed great physical stability. • The nano-selenium in Pickering emulsion was skin permeable in vivo. [ABSTRACT FROM AUTHOR]

Brain structure segmentation in Magnetic Resonance image (MRI) plays an important role in the diagnosis of various neuropsychiatric diseases. Recently, the high cost of manual annotation has motivated research in medical image analysis to focus on unsupervised learning methods. As a promising solution, unsupervised domain adaptation (UDA) has received increasing attention in various medical image segmentation tasks. In this work, we propose a novel UDA framework for brain structure segmentation from MRI volumes. Specifically, we design a self-training-based network architecture to learn cross-domain representations, which is achieved by transferring essential knowledge from a well-trained cumbersome teacher network to a non-trained compact student network using distillation learning technology. The pseudo-labels generated by the pre-trained student model are used to supervise the domain adaptation process of the teacher model. Furthermore, we develop a mutual information maximization alignment module to learn domain-invariant features and cross-domain segmentation knowledge, in which contrastive learning techniques are utilized to maximize the correlation between samples. Finally, we build a unified distillation framework by integrating mutual information distillation and output map distillation, correcting pseudo-labels during the self-training stage, and continuously refining the final predictions of compact networks. Extensive experiments conducted on two datasets with vastly different styles and settings demonstrate that our method is effective in improving segmentation performance on unlabeled target images, and outperforms the state-of-the-art domain adaptation approaches by a large margin. The source code is available at https://github.com/huqian999/UDA-MIMA. • Addresses performance degradation of deep neural networks deployed to unlabeled data. • Combining image, feature, and output alignments facilitates unsupervised cross-domain brain structure segmentation. • Mutual information maximization alignment contributes to domain-invariant features mining and retention. • Knowledge distillation to a self-supervised pretrained model further boosts the performance. [ABSTRACT FROM AUTHOR]

Functional polyesters with good biocompatibility are always important biomaterials. In this study, poly (latide- co - N -trityl serine ester)s (P (LA- co -TSL)s) were synthesized through the copolymerization of lactide (LA) and N -trityl serine lactone (TSL) in toluene under 90 °C with the catalysis of diethylzinc. The molecular weight (Mn) of P (LA- co -TSL) with different TSL molar ratios (4.5%, 8.8%, 25.2%, 41.7% and 100 mol%) ranged from 3.7 kDa to 7.2 kDa with the polydipersity index (PDI) from 1.40 to 1.57. The chemical structure of poly (LA- co -TSL)s was characterized by FTIR, 1H NMR and 13C NMR spectroscopy. As the proportion of TSL in P (LA- co -TSL) increased, the glass transition temperature (Tg) of P (LA- co -TSL) increased gradually, from 56 °C of PLA to 161 °C of Poly (TSL). The initial weitht loss temperature of P (LA- co -TSL) increased as the ratio of TSL increased, from 172 °C of PLA to 230 °C of Poly (TSL). Upon removal of the N -trityl protecting group, amino functional poly (latide- co -serine ester) (P (LA-co-SL)) was realized and confirmd by FTIR and 1H NMR spectra. GPC displayed approximately 19.5% polyester backbone degradation during deprotection with trifluoroacetic acid. DSC analysis illustrated better crystallization properties of the copolyester after amino group deprotection. Using mPEG as an initiator, a new type of block copolymer, mPEG- b -poly (latide- co - N -trityl serine ester)s (mPEG- b -P (LA- co -TSL)s), was obtained. After N -trityl removal, mPEG- b -P (LA- co -TSL) displayed excellent cytocompatibility in L929 cell culture experiments. [Display omitted] • Polyesters with lateral amino-functional groups derived from serine were synthesized and characterized. • Lactide and N -trityl-serine lactone monomers are distributed disorderly along the polyester backbone. • Cell culture experiments demonstrated the excellent cytocompatibility of mPEG- b -poly (lactide- co -serine ester)s. [ABSTRACT FROM AUTHOR]

Background and Aims: High hemoglobin A1c (HbAlc) level is associated with increased cardiovascular disease risk and thromboembolic events [1]. The study sought to explored the association between HbAlc and left atrial appendage flow velocity (LAAV) among non-valvular atrial fibrillation (AF) patients.Methods and Results: A total of 249 consecutive non-valvular AF patients who underwent transesophageal echocardiography (TEE) were divided into two subgroups according to the median of LAAV level (<45 cm/s, ≥45 cm/s). Blood samples and other baseline clinical data of all patients were collected and analyzed. The low LAAV group included 126 patients and the high LAAV group included 123 patients. Patients in the low LAAV group were older and had a higher percentage of persistent AF, chronic heart failure, and higher CHA2DS2-VASc score (P < 0.05). HbAlc level in the low LAAV group was significantly higher than the high LAAV group [6.1 (5.7-6.5)% vs 5.9 (5.6-6.2)%, P = 0.010]. The low LAAV group had larger left atrial diameter (LAD), left atrial area (LAA), higher left atrial pressure (LAP), and lower left ventricular ejection fraction (LVEF) (P < 0.05). Spearman rank correlation analysis showed that the HbAlc level was negatively correlated with LAAV (r = -0.211, P = 0.001). Multivariate analysis indicated that female gender (OR = 2.233, 95% CI 1.110-4.492, P = 0.024), persistent AF (OR = 6.610, 95% CI 3.109-14.052, P < 0.001), and HbAlc (OR = 1.903, 95% CI 1.092-3.317, P = 0.023) were independent factors that associated with low LAAV in AF patients.Conclusion: Increased HbAlc level is associated with decreased LAAV and may reflect a low contractile function of the left atrial appendage. [ABSTRACT FROM AUTHOR]

A human homologue of Saccharomyces cerevisiae Rad1 was isolated and tested for possible correcting activity in defects in Xeroderma pigmentosum (XP) F and rodent 4 and 11 cells. Rad1 was able to correct the defects by performing nucleotide excision repair (NER) of the damaged strands. Purification of the XPF protein revealed that NER took place in the 5' region of DNA and that it required a structure-specific DNA repair endonuclease.

In recent years, researchers have prepared glass-ceramics using a mixture of multiple solid waste materials, which is an effective and resourceful way to use and store solid waste. However, solid waste usually contains multiple heavy metals, which presents challenges during the mixing and co-solidification processes. In this study, high-performance glass-ceramics with low leaching were prepared from blast furnace slag (BFS). The synergistic curing mechanism of BFS glass-ceramics for heavy metals Cr, Mn, Cu, Zn, Ni, and Co was investigated in detail, as well as the migration pattern and storage state of heavy metals under different heat treatment stages and different Cr contents. The results show that the increases in temperature and Cr 2 O 3 content contribute to the incorporation of heavy metals into the crystal lattice and promote crystal growth. Excessive crystallization of spinel causes aggregation, which further curtails the leaching of heavy metals. The leaching concentration of heavy metals mainly depends on the heavy metal content in the glass network and the degree of network polymerization. Thus, spinel acts as a crystal core for the solidification of heavy metals, while augite and glass phases act as a double barrier to physically encapsulate them, which is effective for the storage of a wide range of heavy metals. Furthermore, the physical and chemical properties of BFS glass-ceramics are consistent with the Chinese industry standard "Glass-ceramics plate for industrial application" (JC/T 2097-2011). This study provides important theoretical support for the synergistic solidification of multiple heavy metals in glass-ceramics, as well as insights into the preparation of glass-ceramics by mixing BFS with other solid wastes. [Display omitted] [ABSTRACT FROM AUTHOR]

Sea cucumber Apostichopus japonicus displays the typical circadian rhythms. This present study investigated the molecular regulation of clock genes, as well as monoamines and melatonin, in multiple tissues of A. japonicus , responding to the photoperiod. In order to determine their pivotal role in circadian rhythms, the crucial clock genes, namely AjClock , AjArnt1 , AjCry1 , and AjTimeless , were identified and a comprehensive analysis of their expressions across various tissues in adult A. japonicus was conducted, revealing the potential existence of central and peripheral oscillators. Results demonstrated that the tissues of polian vesicle and nerve ring exhibited significant clock gene expression associated with the orchestration of circadian regulation, and that environmental light fluctuations exerted influence on the expression of these clock genes. However, a number of genes, such as AjArnt1 and AjCry1 , maintained their circadian rhythmicity even under continuous light conditions. Moreover, we further investigated the circadian patterns of melatonin (MT), serotonin (5-HT), and dopamine (DA) secretion in A. japonicus , data that underscored the tissue-specific regulatory differences and the inherent adaptability to dynamic light environments. Collectively, these findings will provide the molecular mechanisms controlling the circadian rhythm in echinoderms and the candidate tissues playing the role of central oscillators in sea cucumbers. [Display omitted] • The molecular circadian system was identified in Apostichopus japonicus. • The polian vesicle and nerve ring were determined with roles as circadian oscillators. • A. japonicus circadian system exhibits stability. • The rhythmicity of molecular circadian system can be affected by photoperiods. [ABSTRACT FROM AUTHOR]

Innate immune memory of macrophages is closely linked to histone modifications. While various studies have demonstrated that the polysaccharide of Asparagus cochinchinensis (Lour.) Merr (ACMP), extracted through alcohol-alkali extraction, enhances macrophages' non-specific immune function; no literature currently addresses whether ACMP's regulatory effect is related to innate immune memory and histone modification. This study aims to investigate if ACMP induces innate immune memory emergence in macrophages via pattern recognition receptor (PRR). After co-incubating different doses of ACMP with RAW264.7 cells and BMDM cells, we observed changes in signaling pathways related to PRR and assessed the presence of innate immune memory phenomenon in the cells. We observed the morphological characteristics of the ACMP using a scanning electron microscope, infrared spectrum, and HPLC pre-column derivatization method. We used q-PCR, Western blot, RNA-seq, and CUT&Tag-seq methods to examine ACMP's regulation of macrophage immune response and innate immune memory and explored its specific mechanism. ACMP, primarily composed of Man, GlcN, Rha, Fuc, GalA, Xyl, Glc, Gal, Ara, and, exhibited a molar ratio of each monosaccharide (1.41: 0.35: 0.49: 0.18: 1.00: 97.12: 0.36: 3.58: 1.14). ACMP regulated immunological function in macrophages through the TLR4-MAPK-JNK/p38/ERK pathway. ACMP induced elevated levels of chromosomal H3K4me1, enhancing TNF-α, IL-1β, and other genes' responsiveness, allowing macrophages to develop innate immune memory to ACMP stimulation. This study first time demonstrates that ACMP regulates immunological function through the TLR4-MAPK-JNK/ERK/p38 signaling pathway, distinct from prior reports. ACMP induces innate immune memory in macrophages in response to its immune stimulation by promoting increased H3K4me1 on chromosomes. This mechanism may be crucial in how plant polysaccharides regulate macrophages and the body's immune function. [Display omitted] [ABSTRACT FROM AUTHOR]

Ionogel electrolytes (IGEs) with chemical and thermal stability properties have attracted considerable attention for all-solid-state energy storage devices, particularly for high-performance supercapacitors (SCs). However, achieving high conductivity, flexibility, and toughness, as well as deformation and impact resistance in special cases, is challenging with the typical polymer based on ionic liquids (ILs). Here, an effective gelation strategy is proposed for the preparation of free-standing LiTFSI/[EMIM][TFSI]/PVDF-HFP ionogels (IGs) by double-additive induced physical cross-linking. The mechanical and electrochemical properties of the IGs can be synergistically optimized by the cross-linking and entanglement of LiTFSI and [EMIM][TFSI] with the PVDF-HFP network. The target IGs simultaneously exhibit excellent deformation capacity (over 50 %), high ionic conductivity (10.3 × 10−3 S cm−1 at 25 °C), hardness (H: 728.6 kPa), and Young's modulus (E: 11.4 MPa), which can exhibit the specific capacitance of 274. 55 F g−1, energy density of 38.13 Wh kg−1 and maximum power density of 2499.93 W kg−1 in the fabricated symmetric supercapacitor. The results will motivate us to further explore their applications for flexible electronic devices, wearable electronic skin, and flexible energy storage. [Display omitted] • The IGE has excellent mechanical strength and deformation ability. • The IGE with high ionic conductivity of 10.5 × 10−3 S cm−1. • The supercapacitor provides higher specific capacitance, energy and power density. • The change of ionic conductivity was verified by molecular dynamics simulation. [ABSTRACT FROM AUTHOR]

The sea cucumber Apostichopus japonicus is an economically important marine species in China, and understanding the mechanisms underlying its gonad development is crucial for successful reproduction and breeding. In this study, we performed transcriptome comparisons and analyses of A. japonicus gonadal and non-gonadal tissues to identify genes and molecular pathways associated with gonadal development. We also supplemented the annotation of the A. japonicus genome. Collectively, results revealed a total of 941 ovary-specific genes and 2499 testis-specific genes through different expression analysis and WGCNA analysis. The most enriched pathways in ovary and testis were "DNA replication" and "purine metabolism", respectively. Additionally, we identified key candidate gene modules that control gonad development and germ cell maturation, with CDT1 and DYNC2LI1 serving as hub genes. Our findings provide important insights into the gonadal development system of A. japonicus and offer valuable references for further research on reproductive biology in this marine invertebrate species. [Display omitted] • Comparative analyses of gene expression in sea cucumber gonadal and non-gonadal tissues • Key candidate gene modules specifically expressed by females and males gonad were screened. • The ovarian module with CDT1 as the core gene may affect ovarian development through the pre-replication complex. [ABSTRACT FROM AUTHOR]