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Abstract Osteoporosis is a metabolic bone disease that involves gradual loss of bone density and mass, thus resulting in increased fragility and risk of fracture. Inflammatory cytokines, such as tumour necrosis factor α (TNF‐α), inhibit osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and several microRNAs are implicated in osteoporosis development. This study aimed to explore the correlation between TNF‐α treatment and miR‐27a‐3p expression in BMSC osteogenesis and further understand their roles in osteoporosis. An osteoporosis animal model was established using ovariectomized (OVX) mice. Compared with Sham mice, the OVX mice had a significantly elevated level of serum TNF‐α and decreased level of bone miR‐27a‐3p, and in vitro TNF‐α treatment inhibited miR‐27a‐3p expression in BMSCs. In addition, miR‐27a‐3p promoted osteogenic differentiation of mouse BMSCs in vitro, as evidenced by alkaline phosphatase staining and Alizarin Red‐S staining, as well as enhanced expression of the osteogenic markers Runx2 and Osterix. Subsequent bioinformatics analysis combined with experimental validation identified secreted frizzled‐related protein 1 (Sfrp1) as a downstream target of miR‐27a‐3p. Sfrp1 overexpression significantly inhibited the osteogenic differentiation of BMSCs in vitro and additional TNF‐α treatment augmented this inhibition. Moreover, Sfrp1 overexpression abrogated the promotive effect of miR‐27a‐3p on the osteogenic differentiation of BMSCs. Furthermore, the miR‐27a‐3p–Sfrp1 axis was found to exert its regulatory function in BMSC osteogenic differentiation via regulating Wnt3a–β‐catenin signalling. In summary, this study revealed that TNF‐α regulated a novel miR‐27a‐3p–Sfrp1 axis in osteogenic differentiation of BMSCs. The data provide new insights into the development of novel therapeutic strategies for osteoporosis.

Regulation of translation is a crucial step in gene expression. Developmental signals and environmental stimuli dynamically regulate translation via upstream small open reading frames (uORFs) and ribosome pausing. Recent studies have revealed many plant genes that are specifically regulated by uORF translation following changes in growth conditions, but ribosome-pausing events are less well understood. In this study, we performed ribosome profiling (Ribo-seq) of etiolated maize (Zea mays) seedlings exposed to light for different durations, revealing hundreds of genes specifically regulated at the translation level during the early period of light exposure. We identified over 400 ribosome-pausing events in the dark that were rapidly released after illumination. These results suggested that ribosome pausing negatively regulates translation from specific genes, a conclusion that was supported by a non-targeted proteomics analysis. Importantly, we identified a conserved nucleotide motif downstream of the pausing sites. Our results elucidate the role of ribosome pausing in the control of gene expression in plants; the identification of the cis-element at the pausing sites provides insight into the mechanisms behind translation regulation and potential targets for artificial control of plant translation.

The density of rockfill material is an important index to evaluate the quality of rockfill dams. It is of great significance to accurately obtain the densities and permeability coefficients of rockfill material dams quickly and accurately by scientific means. However, it takes a long time to measure the permeability coefficient of rockfill material in practice, which means that such measurements cannot fully reflect all the relevant properties. In this paper, using a convolutional neural network (CNN), a machine learning model was established to predict the permeability coefficient of rockfill material with the full scale (d10~d100), pore ratio, Cu, and Cc as the inputs and the permeability coefficient as the output. Through collecting the permeability coefficient and related data in the literature, the set samples were sorted for model training. The prediction results of the trained CNN model are compared with those of the back propagation (BP) model to verify the accuracy of the CNN model. Laboratory constant head penetration experiments were designed to verify the generalization performance of the model. The results show that compared with the BP model, the CNN model has better applicability to the prediction of the permeability coefficient of rockfill material and that the CNN can obtain better accuracy and meet the requirements of the rough estimation of rockfill materials’ permeability in engineering.

The demand for titanium alloy has been increasing in various industries, including aerospace, marine, and biomedical fields, as they fulfilled the need for lightweight, high-strength, and corrosion-resistant material for modern manufacturing. However, titanium alloy has relatively low hardness, poor wear performance, and fatigue properties, which limits its popularization and application. These disadvantages could be efficiently overcome by surface strengthening technology, such as the ultrasonic surface rolling process (USRP). In this study, the true thermo-mechanical deformation behavior of Ti-6Al-4V was obtained by dynamic mechanical experiment using a Hopkinson pressure bar. Moreover, USRP was applied on the Ti-6Al-4V workpiece with different parameters of static forces to investigate the evolution in surface morphology, surface roughness, microstructure, hardness, residual stress, and fatigue performance. The strain rate and temperature during the USRP of Ti-6Al-4V under the corresponding conditions were about 3000 s−1 and 200 °C, respectively, which were derived from the numerical simulation. The correlation between the true thermo-mechanical behavior of Ti-6Al-4V alloy and the USRP parameters of the Ti-6Al-4V workpiece was established, which could provide a theoretical contribution to the optimization of the USRP parameters. After USRP, the cross-sectional hardness distribution of the workpiece was shown to initially rise, followed by a subsequent decrease, ultimately to matrix hardness. The cross-sectional residual compressive stress distribution of the workpiece showed a tendency to initially reduce, then increase, and finally decrease to zero. The fatigue performance of the workpiece was greatly enhanced after USRP due to the effect of grain refinement, work hardening, and beneficial residual compressive stress, thereby inhibiting the propagation of the fatigue crack. However, it could be noted that the excessive static force parameter of USRP could induce the decline in surface finish and compressive residual stress of the workpiece, which eliminated the beneficial effect of the USRP treatment. This indicated that the choice of the optimal USRP parameters was highly crucial. This work would be conducive to achieving high-efficiency and low-damage USRP machining, which could be used to effectively guide the development of high-end equipment manufacturing.

Stochastic differential equations (SDEs) are mathematical models that are widely used to describe complex processes or phenomena perturbed by random noise from different sources. The identification of SDEs governing a system is often a challenge because of the inherent strong stochasticity of data and the complexity of the system’s dynamics. The practical utility of existing parametric approaches for identifying SDEs is usually limited by insufficient data resources. This study presents a novel framework for identifying SDEs by leveraging the sparse Bayesian learning (SBL) technique to search for a parsimonious, yet physically necessary representation from the space of candidate basis functions. More importantly, we use the analytical tractability of SBL to develop an efficient way to formulate the linear regression problem for the discovery of SDEs that requires considerably less time-series data. The effectiveness of the proposed framework is demonstrated using real data on stock and oil prices, bearing variation, and wind speed, as well as simulated data on well-known stochastic dynamical systems, including the generalized Wiener process and Langevin equation. This framework aims to assist specialists in extracting stochastic mathematical models from random phenomena in the natural sciences, economics, and engineering fields for analysis, prediction, and decision making.

Abstract Breast cancer is a heterogenous disease that can be classified into multiple subtypes including the most aggressive basal-like and triple-negative subtypes. Understanding the heterogeneity within the normal mammary basal epithelial cells holds the key to inform us about basal-like cancer cell differentiation dynamics as well as potential cells of origin. Although it is known that the mammary basal compartment contains small pools of stem cells that fuel normal tissue morphogenesis and regeneration, a comprehensive yet focused analysis of the transcriptional makeup of the basal cells is lacking. We used single-cell RNA-sequencing and multiplexed RNA in-situ hybridization to characterize mammary basal cell heterogeneity. We used bioinformatic and computational pipelines to characterize the molecular features as well as predict differentiation dynamics and cell–cell communications of the newly identified basal cell states. We used genetic cell labeling to map the in vivo fates of cells in one of these states. We identified four major distinct transcriptional states within the mammary basal cells that exhibit gene expression signatures suggestive of different functional activity and metabolic preference. Our in vivo labeling and ex vivo organoid culture data suggest that one of these states, marked by Egr2 expression, represents a dynamic transcriptional state that all basal cells transit through during pubertal mammary morphogenesis. Our study provides a systematic approach to understanding the molecular heterogeneity of mammary basal cells and identifies previously unknown dynamics of basal cell transcriptional states.

This paper presents an investigation into the parasitic capacitance of an RF contact scheme for lumped-element EAMs. Test structures are fabricated to analyse this parasitic capacitance via S11 characterisation using a vector network analyser (VNA). Optimisations of the contact scheme lead to the parasitic capacitance being reduced to S11 measurements. These S11 measurements are used to simulate S21 measurements, which predict a f3dB bandwidth of near 80 GHz using an equivalent circuit model.

The bacteria pathogen Xanthomonas oryzae pv. oryzae (Xoo) infects rice and causes the severe disease of rice bacteria blight. As the central regulator of the salic acid (SA) signaling pathway, NPR1 is responsible for sensing SA and inducing the expression of pathogen-related (PR) genes in plants. Overexpression of OsNPR1 significantly increases rice resistance to Xoo. Although some downstream rice genes were found to be regulated by OsNPR1, how OsNPR1 affects the interaction of rice-Xoo and alters Xoo gene expression remains unknown. In this study, we challenged the wild-type and OsNPR1-OE rice materials with Xoo and performed dual RNA-seq analyses for the rice and Xoo genomes simultaneously. In Xoo-infected OsNPR1-OE plants, rice genes involved in cell wall biosynthesis and SA signaling pathways, as well as PR genes and nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes, were significantly upregulated compared to rice variety TP309. On the other hand, Xoo genes involved in energy metabolism, oxidative phosphorylation, biosynthesis of primary and secondary metabolism, and transportation were repressed. Many virulence genes of Xoo, including genes encoding components of type III and other secretion systems, were downregulated by OsNPR1 overexpression. Our results suggest that OsNPR1 enhances rice resistance to Xoo by bidirectionally regulating gene expression in rice and Xoo.

Separation of 99TcO4 − from nuclear waste at the Savannah River Site is hampered by the extreme conditions. Here, the authors propose a solution by developing an alkaline-resistant metal organic framework material featuring unique recognition sites for selective incorporation of 99TcO4 − anions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Summary: The Mammary gland undergoes complicated epithelial remodeling to form lobuloalveoli during pregnancy, in which basal epithelial cells remarkably increase to form a basket-like architecture. However, it remains largely unknown how dormant mammary basal stem/progenitor cells involve in lobuloalveolar development. Here, we show that Nfatc1 expression marks a rare population of mammary epithelial cells with the majority being basal epithelial cells. Nfatc1 reporter-marked basal epithelial cells are relatively dormant mammary stem/progenitor cells. Although Nfatc1 reporter-marked basal epithelial cells have limited contribution to the homeostasis of mammary epithelium, they divide rapidly during pregnancy and contribute to lobuloalveolar development. Furthermore, Nfatc1 reporter-marked basal epithelial cells are preferentially used for multiple pregnancies. Using single-cell RNA-seq analysis, we identify multiple functionally distinct clusters within the Nfatc1 reporter-marked cell-derived progeny cells during pregnancy. Taken together, our findings underscore Nfatc1 reporter-marked basal cells as dormant stem/progenitor cells that contribute to mammary lobuloalveolar development during pregnancy.

Context Er Miao San (EMS) is a traditional Chinese medicine composed of Atractylodis Rhizoma and Phellodendri Cortex in a 1:1 weight ratio. EMS has been used to treat rheumatism in China for many years. Objective To evaluate the anti-arthritic activity of EMS extract on adjuvant-induced arthritis (AA) in Sprague-Dawley rats and to clarify its mechanisms of action. Materials and methods EMS (0.75, 1.5 and 3 g/kg, once daily) was orally administered from day 18 after immunization to day 31. The effects of EMS on AA rats were evaluated by histopathological examination, paw swelling and polyarthritis index. The proliferation of fibroblast-like synoviocyte (FLS) and T cells was detected by CCK-8. The percentages of Th17 cells and Treg cells in splenocytes were determined by flow cytometry. Levels of cytokines in serum were detected by ELISA. Results EMS treatment significantly decreased the paw volume (from 1.20 to 0.81), polyarthritis index (from 9.56 to 4.46) and alleviated ankle joint histopathology in AA rats. EMS inhibited the proliferation of FLS and T cells. Furthermore, EMS treatment decreased Th17 cells (from 4.62 to 2.08%) and increased Treg cells (from 2.77 to 4.75%) in splenocytes. The levels of IL-17A, TNF-α and IL-6 were remarkably decreased in the serum of EMS-treated rats, whereas the levels of IL-10 and TGF-β1 were significantly increased. Conclusions EMS exhibits anti-arthritic activity in the AA model by regulating the balance of cytokines and the ratio of Th17 and Treg cells. These insights may provide an experimental basis for the clinical treatment of RA.

In vivo decorporation of U(VI) from bones is an unsolved challenge because of the formation of stable uranium phosphate complexes. Here, the authors develop a hydroxypyridonone-based ligand with strong uranium complexation and low cytotoxicity. They find this ligand effectively removes uranium from kidney and bones in mice, and is suitable for oral administration.

The therapeutic efficiency of ascorbate is limited by its slow autoxidation. Here, the authors show the application of concave-structured palladium nanocrystals for the treatment of colorectal cancer through the oxidation of ascorbate, enhancing the production of oxidative stresses specifically on cancer cells.

Summary: The mammary epithelial cell (MEC) system is a bilayered ductal epithelium of luminal and basal cells, maintained by a lineage of stem and progenitor populations. Here, we used integrated single-cell transcriptomics and chromatin accessibility analysis to reconstruct the cell types of the mouse MEC system and their underlying gene regulatory features in an unbiased manner. We define differentiation states within the secretory type of luminal cells, which forms a continuous spectrum of general luminal progenitor and lactation-committed progenitor cells. By integrating single-cell transcriptomics and chromatin accessibility landscapes, we identify cis- and trans-regulatory elements that are differentially activated in the specific epithelial cell types and our newly defined luminal differentiation states. Our work provides a resource to reveal cis/trans-regulatory elements associated with MEC identity and differentiation that will serve as a reference to determine how the chromatin accessibility landscape changes during breast cancer.

The article below presents a review of current research on silicon photonics. Herein, an overview of current silicon modulator types and modern integration approaches is presented including direct bonding methods and micro-transfer printing. An analysis of current state of the art silicon modulators is also given. Finally, new prospects for III–V-silicon integration are explored and the prospects of an integrated modulator compatible with current CMOS processing is investigated.

Summary: Our knowledge of transcriptional heterogeneities in epithelial stem and progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem and progenitor potential, but a comprehensive dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses predict a quasi-linear differentiation hierarchy where basal cells progress from Col17a1Hi/Trp63Hi state to early-response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal transcriptional states. Our study provides a systematic view of epidermal cellular dynamics, supporting a revised “hierarchical-lineage” model of homeostasis. : Haensel et al. performed a comprehensive dissection of the cellular makeup of skin during homeostasis and wound healing and the molecular heterogeneity and cellular dynamics within its stem-cell-containing epidermal basal layer. Their work provides insights and stimulates further investigation into the mechanism of skin maintenance and repair. Keywords: single-cell RNA sequencing, skin, stem cell, epidermis, wound healing, metabolism, basal cell state, cellular transition dynamics, FLIM, plasticity

Direct removal of 99TcO4 − from highly radioactive and acidic nuclear waste solutions is beneficial for uranium and plutonium recovery and radioactive pollution control but this represents a huge challenge. Here the authors show a cationic polymeric network with high 99TcO4 − sorption capability and stability.

MicroRNA160 plays a crucial role in plant development by negatively regulating the auxin response factors (ARFs). In this manuscript, we design an automatic molecule machine (AMM) based on the dual catalytic hairpin assembly (D-CHA) strategy for the signal amplification detection of miRNA160. The detection system contains four hairpin-shaped DNA probes (HP1, HP2, HP3, and HP4). For HP1, the loop is designed to be complementary to miRNA160. A fragment of DNA with the same sequences as miRNA160 is separated into two pieces that are connected at the 3′ end of HP2 and 5′ end of HP3, respectively. In the presence of the target, four HPs are successively dissolved by the first catalytic hairpin assembly (CHA1), forming a four-way DNA junction (F-DJ) that enables the rearrangement of separated DNA fragments at the end of HP2 and HP3 and serving as an integrated target analogue for initiating the second CHA reaction, generating an enhanced fluorescence signal. Assay experiments demonstrate that D-CHA has a better performance compared with traditional CHA, achieving the detection limit as low as 10 pM for miRNA160 as deduced from its corresponding DNA surrogates. Moreover, non-target miRNAs, as well as single-base mutation targets, can be detected. Overall, the D-CHA strategy provides a competitive method for plant miRNAs detection.

Cationic metal-organic frameworks provide promising opportunities to capture anionic pollutants, but stable frameworks with sufficiently large pores are lacking. Here the authors present a thorium-based mesoporous, cationic and hydrolytically-stable MOF that can rapidly trap inorganic and organic anionic pollutants.

MicroRNAs play an important role in stem cell fate and tumorigenesis. In this work, the authors show that miR-31 controls mammary stem cell self-renewal and tumorigenesis by simultaneously activating Wnt/β-catenin and repressing TGFβ signaling pathways.

Zirconium phosphonate based metal-organic frameworks often exhibit superior chemical stabilities, but typically exist as poorly crystalline or amorphous materials. Here the authors exploit an ionothermal method to obtain highly porous and remarkably stable single crystalline zirconium phosphonate frameworks that can efficiently remove uranyl ions from aqueous solutions.

The severe work hardening phenomenon generated in the machining of Inconel 718 is harmful to continue cutting processes, while being good for the component’s service performance. This paper investigates the performance of cryogenic assisted machining used in the cutting processes, which can reduce the waste of fluids. The influence of dry and cryogenic machining conditions with different cutting speeds on the work hardening layer is investigated based on the interrupted cutting of Inconel 718. Cutting temperature distribution obtained from simulations under different conditions is used to discuss the potential mechanism of work hardening. Then, the depth of work hardening and degree of work hardening (DWH) are investigated to analyze the surface deformation behavior, which strengthens the machined surface during metal cutting processes. From the cutting experiments, the depth of the work hardening layer can reach more than 60 μm under the given cutting conditions. In addition, a deeper zone can be obtained by the cooling of liquid nitrogen, which may potentially enhance the wear performance of the component. The results obtained from this work can be utilized to effectively control the work hardening layer beneath the surface, which can be applied to improve the service performance.

First-principles calculations were performed to investigate the effects of boron/nitrogen dopant on the geometry, electronic structure and magnetic properties of the penta-graphene system. It was found that the electronic band gap of penta-graphene could be tuned and varied between 1.88 and 2.12 eV depending on the type and location of the substitution. Moreover, the introduction of dopant could cause spin polarization and lead to the emergence of local magnetic moments. The main origin of the magnetic moment was analyzed and discussed by the examination of the spin-polarized charge density. Furthermore, the direction of charge transfer between the dopant and host atoms could be attributed to the competition between the charge polarization and the atomic electronegativity. Two charge-transfer mechanisms worked together to determine which atoms obtained electrons. These results provide the possibility of modifying penta-graphene by doping, making it suitable for future applications in the field of optoelectronic and magnetic devices.

The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.

Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6′-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck. Human CD4+ T cells were purified from peripheral blood mononuclear cells using microbeads. T cell viability and proliferation were detected by Cell Counting Kit-8 and CFSE Cell Proliferation Kit. Cytokines secreted by T cells were assessed with the Quantibody Human Inflammation Array. The binding affinity and expression of IgDR on T cells were detected by flow cytometry, and protein expression of IgDR, Lck, and P-Lck were analyzed by western blot. IgD was shown to bind to IgDR on CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394). CP-25 inhibited the IgD-stimulated activation and proliferation of CD4+ T cells, as well as the production of inflammatory cytokines; it was thus suggested that this process might be related to the downregulation of Lck (Tyr394) phosphorylation. These results demonstrate that IgD amplifies the activation of CD4+ T cells, which could be mediated by Lck phosphorylation. Further, CP-25, via its ability to modulate Lck, is a novel potential therapeutic agent for the treatment of human autoimmune diseases.

Immunoglobulin D (IgD) is a surface immunoglobulin that is expressed as either membrane IgD (mIgD) or secreted IgD (sIgD). Researchers have shown that sIgD is often elevated in patients with autoimmune diseases. The possible roles of sIgD on the function of peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) are still unclear. In this study, we compared the expression of sIgD, mIgD and IgD receptor (IgDR) in RA patients and healthy controls, and investigated the effect of sIgD on the function of PBMCs. We found that the levels of sIgD, mIgD and IgDR were significantly higher in RA patients compared with healthy controls. The concentrations of sIgD were positively correlated with soluble receptor activator of nuclear factor-κB ligand (sRANKL), rheumatoid factor (RF) and C-reactive protein (CRP) in RA patients. Strikingly, IgD could enhance the proliferation of PBMCs and induce IL-1α, IL-1β, TNF-α, IL-6 and IL-10 production from PBMCs. Moreover, the percentage of activated T cell subsets (CD4+CD69+, CD4+CD154+) and activated B cell subsets (CD19+CD23+, CD19+CD21+, CD19+IgD+ and CD19-CD138+) were increased by IgD. The percentage of unactivated T cell subset (CD4+CD62L+) and immature B cell subset (CD19+IgM+IgD-) were decreased by IgD in PBMCs. Furthermore, the expressions of IgDR on T and B cells were significantly increased by treatment with IgD. Our results demonstrate that IgD enhanced the activation of PBMCs, which may contribute to RA pathogenesis. Therefore, IgD could be a potential novel immunotherapeutic target for the management of RA.

A novel and practical self-calibration method for misaligned non-central catadioptric cameras is proposed in this paper. Without the aid of any special calibration patterns in the scene, the developed method is able to automatically estimate the pose parameters of the mirror with respect to the perspective camera. First it uses the ellipse corresponding to the mirror boundary in the image to compute the possible solutions for mirror postures. With two pose candidates, thereafter we propose a novel selection method to find the correct solution by using the image of the lens boundary. The whole calibration process is automatic and convenient to carry out since nothing more than a single image acquired from the catadioptric camera is needed. Experimental results both on synthesized and real images prove our success.

Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach integrating modeling and experiments, we found multiple intermediate states contributing to EMT and that the robustness of the transitions is modulated by transcriptional factor Ovol2. In particular, we obtained evidence for a mutual inhibition relationship between Ovol2 and EMT inducer Zeb1, and observed that adding this regulation generates a novel four-state system consisting of two distinct intermediate phenotypes that differ in differentiation propensities and are favored in different environmental conditions. We identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to be critical in achieving and selecting between intermediate states. Our analysis suggests a new design principle in controlling cellular plasticity through multiple intermediate cell fates and underscores the critical involvement of Ovol2 and its associated molecular regulations.

Extensive genomic diversity has been observed among hepatitis E virus (HEV) strains. However, the implication of the genetic heterogeneity on HEV antigenic properties is uncertain. In this study, monoclonal antibodies (Mabs) against truncated ORF2-encoded proteins (aa452‑617, designated p166 proteins) derived from HEV strains of Burma (genotype 1a, p166Bur), Pakistan (1b, p166Pak) and Morocco (1c, p166Mor) were raised and used for identification of HEV antigenic diversity. Six Mabs reacted to these 3 p166 proteins as well as p166 proteins constructed from strains derived from Mexico (genotype 2), US (genotype 3) and China (genotype 4), indicating the existence of pan‑genotypic epitopes. Two Mabs, 1B5 and 6C7, reacted with p166Bur and p166Mor, but not p166Pak or p166s derived from genotypes 2, 3, and 4, indicating that these 2 Mabs recognized strain-specific HEV epitopes. Both the common and specific epitopes could not be mapped by 23 synthetic peptides spanning the p166Bur sequence, suggesting that they are confirmation‑dependent. Comparative sequence analysis showed that p166Bur and p166Mor shared an identical aa sequence along their entire lengths, whereas for p166Pak the aas occupying positions 606 and 614 are different from aas at corresponding positions of p166Bur and p166Mor. Reactivity between 1B5 and p166Bur was abrogated with mutation of p166Bur/A606V, whereas p166Pak acquired the reactivity to 1B5 with mutation of p166Pak/V606A. However, mutations of p166Bur/L614M and P166Pak/M614L did not affect the immunoreactivity. Therefore, the aa occupying position 606 plays a critical role in maintaining the antigenicity of the HEV p166 proteins.

During 2001–2011, hepatitis E virus (HEV) was found in the blood of patients in Nanjing, China. All HEV-positive patients had virus genotype 4; subgenotype 4a was predominant. The effective population of HEV in Nanjing increased in ≈1980 and continued until ≈2003 when it plateaued.

Mammary gland branching morphogenesis and ductal homeostasis relies on mammary stem cell function for the maintenance of basal and luminal cell compartments. The mechanisms of transcriptional regulation of the basal cell compartment are currently unknown. We explored these mechanisms in the basal cell compartment and identified the Co-factor of LIM domains (CLIM/LDB/NLI) as a transcriptional regulator that maintains these cells. Clims act within the basal cell compartment to promote branching morphogenesis by maintaining the number and proliferative potential of basal mammary epithelial stem cells. Clim2, in a complex with LMO4, supports mammary stem cells by directly targeting the Fgfr2 promoter in basal cells to increase its expression. Strikingly, Clims also coordinate basal-specific transcriptional programs to preserve luminal cell identity. These basal-derived cues inhibit epidermis-like differentiation of the luminal cell compartment and enhance the expression of luminal cell-specific oncogenes ErbB2 and ErbB3. Consistently, basal-expressed Clims promote the initiation and progression of breast cancer in the MMTV-PyMT tumor model, and the Clim-regulated branching morphogenesis gene network is a prognostic indicator of poor breast cancer outcome in humans.

Deregulation of canonical Wnt/CTNNB1 (beta-catenin) pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are highly frequent in colon cancer and cause aberrant stabilization of CTNNB1, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of CTNNB1 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of CTNNB1 in colon cancer cells.We observed 3629 CTNNB1 binding peaks across the genome and a significant correlation between CTNNB1 binding and knockdown-induced gene expression change. Our integrative analysis led to the discovery of a direct Wnt target signature composed of 162 genes. Gene ontology analysis of this signature revealed a significant enrichment of Wnt pathway genes, suggesting multiple feedback regulations of the pathway. We provide evidence that this gene signature partially overlaps with the Lgr5+ intestinal stem cell signature, and is significantly enriched in normal intestinal stem cells as well as in clinical colorectal cancer samples. Interestingly, while the expression of the CTNNB1 target gene set does not correlate with survival, elevated expression of negative feedback regulators within the signature predicts better prognosis.Our data provide a genome-wide view of chromatin occupancy and gene regulation of Wnt/CTNNB1 signaling in colon cancer cells.

BackgroundThe identification of hepatitis E virus (HEV) from rabbits motivated us to assess the possibility of using rabbits as a non-human primate animal model for HEV infection and vaccine evaluation.Methodology/principal findingsFirst, 75 rabbits were inoculated with seven strains of genotypes 1, 3, 4, and rabbit HEV, to determine the appropriate strain, administrative route and viral dosage. Second, 15 rabbits were randomly divided into three groups and vaccinated with 0 µg (placebo), 10 µg and 20 µg of HEV candidate vaccine, HEV p179, respectively. After three doses of the vaccination, the rabbits were challenged with 3.3×10(5) genome equivalents of genotype 4 HEV strain H4-NJ703. The strain of genotype 1 HEV was not found to be infectious for rabbits. However, approximately 80% of the animals were infected by two rabbit HEV strains. All rabbits inoculated with a genotype 3 strain were seroconverted but did not show viremia or fecal viral shedding. Although two genotype 4 strains, H4-NJ153 and H4-NJ112, only resulted in part of rabbits infected, another strain of genotype 4, H4-NJ703, had an infection rate of 100% (five out of five) when administrated intravenously. However, only two out of fifteen rabbits showed virus excretion and seroconversion when inoculated orally with H4-NJ703 of three different dosages. In the vaccine evaluation study, rabbits vaccinated with 20 µg of the HEV p179 produced anti-HEV with titers of 1∶10(4)-1∶10(5) and were completely protected from infection. Rabbits vaccinated with 10 µg produced anti-HEV with titers of 1∶10(3)-1∶10(4) and were protected from hepatitis, but two out of the five rabbits showed virus shedding.Conclusions/significanceRabbits may be served as an alternative to the non-human primate models for HEV infection and vaccine evaluation when certain virus strains, appropriate viral dosages, and the intravenous route of inoculation are selected.

Two allyldimethylalkyl quaternary ammonium salt (AQAS) monomers, N,N-dimethylallylphenylpropylammonium bromide (AQAS1) and N,N-dimethylallylnonylammonium bromide (AQAS2), were synthesized and used to prepare modified polyacrylamide materials. Two new drag reducers were synthesized from acrylamide (AM), sodium acrylate (NaAA) and a cationic modified monomer (AQAS1 or AQAS2) via aqueous solution polymerization, and the copolymers were named P(AM/NaAA/AQAS1) and P(AM/NaAA/AQAS2), respectively. The structures of the drag reduction agents were confirmed by IR and 1H NMR spectroscopies. The molecular weight (Mw) of P(AM/NaAA/AQAS1) was 1.79 × 106 g/mol. When the copolymer concentration was 1000 mg/L and the flow rate was 45 L/min, in fresh water the highest drag reduction rate was 75.8%, in 10,000 mg/L NaCl solution the drag reduction rate decreased to 72.9%. The molecular weight of P(AM/NaAA/AQAS2) was 3.17 × 106 g/mol. When the copolymer concentration was 500 mg/L and the flow rate was 45 L/min, the drag reduction rate reached 75.2%, and in 10,000 mg/L NaCl solution the drag reduction rate was 73.3%, decreased by approximately 1.9%. The drag reduction rate for partially hydrolyzed polyacrylamide (HPAM) was also investigated, and the results showed that the drag reduction rates for 500 and 1000 mg/L HPAM solutions were merely 43.2% and 49.0% in brine, respectively. Compared with HPAM, both of the above copolymers presented better drag reduction capacities. © 2024 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. [ABSTRACT FROM AUTHOR]