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The space-based gravitational wave detection mission, TianQin, requires high-level synchronization between independent clocks of all spacecrafts to extract the gravitational wave signals. It is necessary to measure the inter-spacecraft relative clock jitter based on laser phase-sideband clock transfer. The main challenge is the tracking and locking of clock sideband beatnote signals with low signal-to-noise ratio and frequency variation. In this paper, a systematic scheme of inter-spacecraft clock jitter readout is reported. The requirement of the clock transfer link for TianQin based on the time-delay interferometry algorithm is derived. A bi-directional laser interferometer system with a transmission optical power below 1 nW and a time delay of ∼50 µs is built up to demonstrate the weak-light clock transfer. In this scheme, frequency modulation is performed on the laser to simulate the inter-spacecraft Doppler frequency shift and its variation. Based on electrical and optical clock transfer comparison experiments, it is demonstrated that the GHz frequency synthesizer is the main noise source below the 50 mHz frequency range. The residual clock jitter noise introduced by the optical transfer link is below 40 fs/Hz 1/2 above the 6 mHz frequency range, and the fractional frequency instability is less than 6.7 × 10 -17 at 1000 s, which meets the requirement of the TianQin mission. Ultimately, The carrier phase measurement accuracy reaches 1 × 10 -4 cycles/Hz 1/2 above 6 mHz after differential clock noise correction using measured clock jitter.

In the era of digital economy, enterprise research and development (R&D) tends to be open-source. Due to their limited resources, small and medium-sized enterprises (SMEs) can join open-source platforms to get additional creative resources and technical support. In this context, from the perspective of complex networks, the influence diffusion of SMEs after embedding open-source innovation networks is studied in this paper. First, an integrated simulation model including a network model, agent model and innovative diffusion model is constructed. Second, the influence diffusion strategy is proposed considering initial impact, embedding timing and connection mode (same-match and heterogeneous) of the enterprise. Third, the dynamic simulation of the influence diffusion process of SMEs demonstrates that embedding timing has a significant impact. There is no significant difference in the influence diffusion at the early and mature stages in the evolution process of open-source innovation networks. The initial impact of enterprises has a significant influence on the diffusion during the developing period, but the effect on its influence diffusion at the initial and mature stages is not obvious. Finally, in light of experiment results, it is clear that the open-source platform plays an important role on the growth of SMEs as evidenced by the close correlation between the spread of SMEs' influence within the open-source innovation network and the community's stage of development.

Background: Gastric cancer is a common and highly aggressive malignant tumor of the gastrointestinal tract that poses a serious threat to human life and health. As the clinical symptoms of early gastric carcinoma are not obvious, many patients are diagnosed in the middle or late stages. With the advancement of medical technology, gastrectomy has become a safer surgical procedure, but it still has a high recurrence and mortality rate after surgery. The prognosis of gastric cancer patients after surgery is not only related to tumor-related factors (i.e., tumor stage) but the patient's nutritional status. This study aimed to investigate the effect of preoperative muscle mass combined with the prognostic nutritional index (PNI) on clinical prognosis in locally advanced gastric carcinoma., Methods: The clinical data of 136 patients with locally advanced gastric carcinoma diagnosed by pathology and undergoing radical gastrectomy were retrospectively reviewed. To analyze the influencing factors of preoperative low muscle mass and its correlation with the prognostic nutritional index. Patients with both low muscle mass and low PNI (≤46.55) were assigned a score of 2, and those with only one or neither of these abnormalities were assigned a score of 1 or 0, respectively, according to the new prognostic score (PNIS). The relationship between PNIS and clinicopathological characteristics was analyzed. Univariate and multivariate analyses were performed to identify risk factors for overall survival (OS)., Results: Low muscle mass was associated with a lower PNI ( P < 0.01). The optimal cut-off value of PNI was 46.55, the sensitivity was 48%, and the specificity was 97.1%. There were 53 (38.97%), 59 (43.38%), and 24 patients (17.65%) in the PNIS 0, 1, and 2 groups, respectively. A higher PNIS and advanced age were independent risk factors for postoperative complications ( P < 0.01). The overall survival rate in patients with PNIS 2 score was significantly poorer than in patients with scores of 1 or 0 (3-year OS: 45.8% vs 67.8% vs 92.4%, P < 0.001). A Multivariate Cox hazards analysis showed that PNIS 2, depth of tumor invasion, vascular invasion, and postoperative complications were independent predictors of the poor 3-year survival in patients with locally advanced gastric cancer., Conclusions: The combination of muscle mass and the PNI score system can be used to predict the survival outcome of patients with locally advanced gastric cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Hou, Li and Liu.)

Neuromedin U (NMU) has a critical function on the regulation of food intake in mammals, while the information is little in teleost. To investigate the function of NMU on appetite regulation of Siberian sturgeon ( Acipenser baerii ), this study first cloned nmu cDNA sequence that encoded 154 amino acids including NMU-25 peptide. Besides, the results showed that nmu mRNA was widely distributed in various tissues especially in the hypothalamus and telencephalon. The results of nutritional status (pre-feeding and post-feeding, fasting and re-feeding) experiments showed that nmu mRNA expression was significantly decreased at 1 and 3 h after feeding in different brain regions. Similarly, after feeding, the expression of nmu significantly decreased in peripheral tissues. Moreover, nmu expression in the hypothalamus was significantly increased after fasting 1 d, but decreased after fasting 17 d, which was significantly reversed after re-feeding. However, other brain regions like telencephalon and peripheral tissues like oesophagus, intestinum valvula and liver have different change patterns. Further study showed that acute i.c.v. and i.p. injection of NMU and chronic i.p. injection of NMU significantly reduced the food intake in a dose-dependent mode. In addition, the expressions of several critical appetite factors ( nmu , aplein , cart , cck , ghrelin , npy , nucb2 , pyy and ucn3 ) were significantly affected by acute NMU-25 administration in the hypothalamus, intestinum valvula and liver. These results indicate that NMU-25 has the anorexigenic function on food intake by affecting different appetite factors in Siberian sturgeon, which provides a foundation for further exploring the appetite regulation networks in fish.

Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Liu, Li, Zhang, Gao, Zeng and Wang.)

Purpose: Little is known about the host-tumor interaction in the lymph-node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastases of a patient with triple-negative breast cancer., Methods: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during surgery. Single-cell sequencing was performed on all four specimens., Results: 14,016 cells were clustered into 6 cell subpopulations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor-associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8 + and CD4 + T lymphocytes concentrated more in sentinel lymph node and mainly stratified into two transcriptional states. The immune-cell amount variation among primary tumor, sentinel and normal lymph nodes showed a similar tendency between the sc-RNA-seq profile of TNBC samples and a previous reported bulk RNA-seq profile of a breast cancer cohort, including all four breast cancer subtype samples., Discussion: Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity, while other T cells exhibit an exhausted state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between SLND and ALND., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Diet is an important exposure route for phthalates, such as di-iso-butyl phthalate (DiBP), dibutyl phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), and benzyl butyl phthalate (BBP). In this study, we aimed to estimate phthalate exposure in the diet of pregnant women and assess the health risk. A total of 517 pregnant women in the first trimester were recruited, and food frequency questionnaires were collected. A simple distribution assessment method was used to estimate daily exposure, and the hazard index (HI) method was used to assess cumulative risk. The maximum daily dietary exposure to DEHP, DBP, DiBP, and BBP was 5.25, 3.17, 2.59, and 0.58 μg/kg bw/day, respectively, and did not exceed the safety limit values. Cereals and vegetables were the main sources of the estimated daily intake (EDI) of phthalates in the diet. The cumulative risk assessment, based on the European Food Safety Authority tolerable daily intake (TDI) and the US Environmental Protection Agency reference dose (RfD), did not exceed the threshold of 1. DiBP, DBP, and DEHP had higher hazard quotient (HQ) values for cumulative health risk than BBP. In conclusion, a low health risk was posed by the cumulative dietary exposure to phthalates for pregnant women in Beijing., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms., Methods: Sprague-Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms., Results: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female)., Conclusions: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF., (© 2022. The Author(s).)

Reprogrammed cell metabolism is deemed as one of the hallmarks of cancer. Hexosamine biosynthesis pathway (HBP) acts as an "energy sensor" in cells to regulate metabolic fluxes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of HBP, is broadly found with elevated expression in human cancers though its exact and concrete role in tumorigenesis still remains unknown and needs further investigation. P38 mitogen-activated protein kinase (MAPK) is an important component of stress-signaling pathway and plays a critical role in cell fate decision, whereas the underlying mechanism of its activation under nutrient stress also remains elusive. In this study, we show that glucose deprivation induces the interaction of GFAT1 with transforming growth factor β-activated kinase 1 binding protein 1 (TAB1) in a TAB1 S438 phosphorylation-dependent manner. Subsequently, the binding of GFAT1 to TAB1 facilitates TTLL5-GFAT1-TAB1 complex formation, and the metabolic activity of GFAT1 for glutamate production further contributes to TTLL5-mediated TAB1 glutamylation. In consequence, TAB1 glutamylation promotes the recruitment of p38α MAPK and thus drives p38 MAPK activation. Physiologically, GFAT1-TAB1-p38 signaling promotes autophagy occurrence and thus protects tumor cell survival under glucose deficiency. Clinical analysis indicates that both GFAT1 and TAB1 S438 phosphorylation levels correlate with the poor prognosis of lung adenocarcinoma patients. These findings altogether uncover an unidentified mechanism underlying p38 MAPK signaling regulation by metabolic enzyme upon nutrient stress and provide theoretical rationality of targeting GFAT1 for cancer treatment., (© 2022. The Author(s).)

Biaryl scaffolds are privileged templates used in the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets. Biaryls are found in the structures of therapeutics, including antibiotics, anti-inflammatory, analgesic, neurological and antihypertensive drugs. However, existing synthetic routes to biphenyls rely on traditional coupling approaches that require both arenes to be prefunctionalized with halides or pseudohalides with the desired regiochemistry. Therefore, the coupling of drug fragments may be challenging via conventional approaches. As an attractive alternative, directed C-H activation has the potential to be a versatile tool to form para-substituted biphenyl motifs selectively. However, existing C-H arylation protocols are not suitable for drug entities as they are hindered by catalyst deactivation by polar and delicate functionalities present alongside the instability of macrocyclic intermediates required for para-C-H activation. To address this challenge, we have developed a robust catalytic system that displays unique efficacy towards para-arylation of highly functionalized substrates such as drug entities, giving access to structurally diversified biaryl scaffolds. This diversification process provides access to an expanded chemical space for further exploration in drug discovery. Further, the applicability of the transformation is realized through the synthesis of drug molecules bearing a biphenyl fragment. Computational and experimental mechanistic studies further provide insight into the catalytic cycle operative in this versatile C-H arylation protocol., (© 2022. The Author(s).)

Helicobacter pylori is one of the most common pathogenic bacterium worldwide, infecting about 50% of the world's population. It is a major cause of several upper gastrointestinal diseases, including peptic ulcers and gastric cancer. The emergence of H. pylori resistance to antibiotics has been a major clinical challenge in the field of gastroenterology. In the course of H. pylori infection, some bacteria invade the gastric epithelium and are encapsulated into a self-produced matrix to form biofilms that protect the bacteria from external threats. Bacteria with biofilm structures can be up to 1000 times more resistant to antibiotics than planktonic bacteria. This implies that targeting biofilms might be an effective strategy to alleviate H. pylori drug resistance. Therefore, it is important to develop drugs that can eliminate or disperse biofilms. In recent years, anti-biofilm agents have been investigated as alternative or complementary therapies to antibiotics to reduce the rate of drug resistance. This article discusses the formation of H. pylori biofilms, the relationship between biofilms and drug resistance in H. pylori , and the recent developments in the research of anti-biofilm agents targeting H. pylori drug resistance., Competing Interests: The authors declare that they have no conflicts of interest., (© 2022 Hou et al.)

Natural products are small molecules naturally produced by multiple sources such as plants, animals, fungi, bacteria and archaea. They exert both beneficial and detrimental effects by modulating biological targets and pathways involved in oxidative stress and antioxidant response. Natural products' oxidative or antioxidative properties are usually investigated in preclinical experimental models, including virtual computing simulations, cell and tissue cultures, rodent and nonhuman primate animal models, and human studies. Due to the renewal of the concept of experimental animals, especially the popularization of alternative 3R methods for reduction, replacement and refinement, many assessment experiments have been carried out in new alternative models. The model organism Caenorhabditis elegans has been used for medical research since Sydney Brenner revealed its genetics in 1974 and has been introduced into pharmacology and toxicology in the past two decades. The data from C. elegans have been satisfactorily correlated with traditional experimental models. In this review, we summarize the advantages of C. elegans in assessing oxidative and antioxidative properties of natural products and introduce methods to construct an oxidative damage model in C. elegans . The biomarkers and signaling pathways involved in the oxidative stress of C. elegans are summarized, as well as the oxidation and antioxidation in target organs of the muscle, nervous, digestive and reproductive systems. This review provides an overview of the oxidative and antioxidative properties of natural products based on the model organism C. elegans .

Purpose: This study aimed to explore the mutational characteristics and significance of cell cycle-related genes (CCGs) in hormone-receptor positive, human epidermal growth factor receptor 2 negative breast cancer (HR+/HER2- BC)., Methods: A total of 1668 HR+/HER2- BC patients from the Guangdong Provincial People's Hospital (GDPH) cohort (n = 321) and METABRIC cohort (n = 1347) were included. Tumor samples from HR+/HER2- BC patients were collected for a next-generation sequencing assay in GDPH cohort, including 15 key CCGs. The association between CCGs alterations and overall survival were identified via the Cox regression analysis. The functional roles of the CCGs were explored via the Metascape database., Results: Based on multivariate Cox regression analysis, a set of five key CCGs (CDK4, CCND1, CDKN1A, CDKN1C, and CHEK2) were identified as independent prognostic variables in HR+/HER2- BC patients. Besides, the five-CCGs-based risk score was used to effectively classify patients into the low-risk and high-risk groups (P < 0.0001). The potential functional pathways of the CCGs included cell cycle, cyclin D associated events in G1, and regulation of G1/S transition of mitotic cell cycle., Conclusion: We performed the integrated analysis of the CCGs in HR+/HER2- BC patients. It has the potential to guide individualized precision oncology therapeutic schemes in HR+/HER2- BC patients., (© 2021. The Japanese Breast Cancer Society.)

Purpose: We investigated the effects of retinal ischemia, neurodegeneration, and subclinical edema on best-corrected visual acuity (BCVA) in the early stages of diabetic retinopathy (DR)., Methods: Ischemia was evaluated by the microvascular parameters measured by optical coherence tomography angiography. Neurodegeneration and subclinical edema were identified by the intraretinal layer thickness obtained by optical coherence tomography. Eyes with nonproliferative diabetic retinopathy (n = 132) from 89 patients were analyzed. Eyes were classified as having normal BCVA (n = 88 [66.7%], Snellen equivalent ≥ 20/20) or decreased BCVA (n = 44 [33.3%], Snellen equivalent < 20/20). The prevalence of ischemia, neurodegeneration, and subclinical edema was explored in patients with and without decreased BCVA, and correlations between BCVA and these pathological pathways were determined., Results: Vessel density in the deep retinal capillary plexus (DRCP) and thickness of ganglion cell layer plus inner plexiform layer (GCL-IPL) were significantly lower in eyes with decreased BCVA compared with eyes with normal BCVA (both P < 0.05). In the final multiple regression predictive model, age, DRCP vessel density, and GCL-IPL thickness (all P ≤ 0.044) were predictors of BCVA. DRCP vessel density and GCL-IPL thickness have an interactive effect on visual acuity. The proportions of ischemia and neurodegeneration were significantly higher in eyes with decreased BCVA than in eyes with normal BCVA (P = 0.001 and P = 0.004, respectively)., Conclusion: During the natural course of the early stages of DR, ischemia and neurodegeneration were the main disease pathways associated with visual acuity, and the mechanisms varied among patients., (© 2021. The Author(s).)

The exploitation of chirality at silicon in asymmetric catalysis is one of the most intriguing and challenging tasks in synthetic chemistry. In particular, construction of enantioenriched mediem-sized silicon-stereogenic heterocycles is highly attractive, given the increasing demand for the synthesis of novel functional-materials-oriented silicon-bridged compounds. Here, we report a rhodium-catalyzed enantioselective construction of six- and seven-membered triorgano-substituted silicon-stereogenic heterocycles. This process undergoes a direct dehydrogenative C-H silylation, giving access to a wide range of triorgano-substituted silicon-stereogenic heterocycles in good to excellent yields and enantioselectivities, that significantly enlarge the chemical space of the silicon-centered chiral molecules. Further elaboration of the chiral monohydrosilane product delivers various corresponding tetraorgano-substituted silicon-stereogenic heterocycles without the loss of enantiopurity. These silicon-bridged heterocycles exhibit bright blue fluorescence, which would have potential application prospects in organic optoelectronic materials.

An unprecedented dearomatized spirocyclopropane intermediate was discovered in a sequential Cp*Rh III -catalyzed C-H activation and Wagner-Meerwein-type rearrangement reaction. How the oxidative O-N bond is cleaved and the role of HOAc were uncovered in this study. Furthermore, a Cp*Rh III -catalyzed dearomatization reaction of N-(naphthalen-1-yloxy)acetamide with strained olefins was developed, affording a variety of spirocyclopropanes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Previous direct C-H nitrogenation suffered from simple amidation/amination with limited atom-economy and is mostly limited to C(sp(2) )-H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp(2) )-H and C(sp(3) )-H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Although much research has been conducted on the impact of strabismus on the quality of life (QoL) of adults, the effect of this condition on teenagers has not been extensively studied. This study therefore aimed to assess the effect of strabismus on the vision-related QoL of Chinese teenagers., Methods: The Chinese version of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) was self-administered by 1,040 teenagers with strabismus and 1,002 individuals with normal vision. All the participants were from the Chinese Han population. The independent samples t-test was used to compare QoL between teenagers with and without strabismus., Results: The majority of scores on the NEI-VFQ-25 domains were significantly different between the two groups. QoL was significantly lower in individuals with strabismus compared with teenagers with normal vision on all domains, with the exception of social functioning., Conclusion: Statistically significantly lower vision-related QoL scores were found in Chinese Han teenagers with strabismus compared with those without strabismus.

Recent interest in high-precision positioning stages with large travel ranges has sparked renewed attention to the development of voice coil motors (VCMs). Due to their large output force, VCMs can actuate more complicated flexure structures, eliminate rail friction, and improve positioning speed. The VCM structure is both compact and flexible; hence, it is convenient to design VCMs for a variety of stage structures. Furthermore, VCMs combined with other actuators are able to achieve large travel ranges with high precision. In this paper, we summarize the principles and control methods of a typical VCM, and we analyze its properties, including thrust force, acceleration, and response time. We then present recent research on high-precision VCM positioning stages with large travel ranges.

Understanding the dynamics of cell population allows insight into the control mechanism of the growth and development of mammalian tissues. It is well known that the proliferation and differentiation among stem cells (SCs), intermediate progenitor cells (IPCs), and fully differentiated cells (FDCs) are under different activation and inhibition controls. Secreted factors in negative feedback loops have already been identified as major elements in regulating the numbers of different cell types and in maintaining the equilibrium of cell populations. We have developed a novel spatial dynamic model of cells. We can characterize not only overall cell population dynamics, but also details of temporal-spatial relationship of individual cells within a tissue. In our model, the shape, growth, and division of each cell are modeled using a realistic geometric model. Furthermore, the inhibited growth rate, proliferation and differentiation probabilities of individual cells are modeled through feedback loops controlled by secreted factors of neighboring cells within a proper diffusion radius. With specific proliferation and differentiation probabilities, the actual division type that each cell will take is chosen by a Monte Carlo sampling process. With simulations we found that with proper strengths of inhibitions to growth and stem cell divisions, the whole tissue is capable of achieving a homeostatic size control. We discuss our findings on control mechanisms of the stability of the tissue development. Our model can be applied to study broad issues on tissue development and pattern formation in stem cell and cancer research.

Regulation of cell growth and proliferation has a fundamental role in tissue development, organogenesis, and disease progression. Conserved distribution of the number of sides of cells with a mean value of six was found in a variety of proliferating epithelia. Previous studies have shown that clones of proliferating cells bounded by quiescent cells have fewer sides than normal epithelia. However, the mechanisms for mediating such localized topological change remain poorly understood. In this study, we use a two-dimensional vertex model with consideration of mechanical forces to investigate how differential proliferation and forces can influence cell shape and tissue morphogenesis, and how they may lead to distorted topological change. We find that differential proliferation alone is insufficient to affect the topology of boundary proliferating cells. Rather, increased surface tension on the boundary, in addition to differential proliferation, can significantly decrease the average number of cell sides. Our results are consistent with experimental observations. We conclude that mechanical forces in addition to localized differential proliferation are required to produce the distorted topological change which significantly impacts the overall cell shape and tissue morphogenesis.

Serum proteomics provides a useful tool to identify potential biomarkers associated with cancer progression. In the present study, a two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) on a linear ion trap was utilized to identify and compare serum proteins from breast cancer patients. Three groups of 21 human sera, 7 from patients with lymph node-negative invasive ductal carcinoma (IDCB), 7 from patients with lymph node-positive IDCB, and 7 controls from patients with benign breast diseases, were analyzed. Through proteomic analysis, a total of 2,078 proteins were identified with at least two unique peptide hits. By quantification with label-free spectral counting, a fruitful list of serum proteins with significant differences in abundance accompanying the progression of breast cancer was found. Through hierarchical cluster analysis based on the differently expressed proteins in selection, we found that different groups of sera could be distinguished. Among the selected proteins, tenascin-XB (TNXB) was further validated by the ELISA method in 131 serum samples as a promising biomarker for early metastasis of breast cancer. These experiments revealed the valuable potential of label-free quantitative 2D-LC-MS/MS for identification of novel biomarkers for disease progression.