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Circadian function and p53 network are interconnected on the molecular level, but the dynamics induced by the interaction between the circadian factor Per2 and the tumor suppressor p53 remains poorly understood. Here, we constructed an integrative model composed of a circadian clock module and a p53-Mdm2 feedback module to study the dynamics of p53-Per2 network in unstressed cells. As expected, the model can accurately predict the circadian rhythm, which is consistent with diverse experimental observations. In addition, using a combination of theoretical analysis and numerical simulation, the results demonstrated that p53 expression enhances the phase advance of circadian rhythm and reduces the robustness of circadian rhythm. Furthermore, the time delay required for the transcription and translation of Per2 protein induces oscillations by undergoing a supercritical Hopf bifurcation, and improves the robustness of circadian rhythm. In summary, this work shows that the p53-Per2 interaction and the time delay are two essential factors for circadian functions. [ABSTRACT FROM AUTHOR]

To assess and quantify sarcopenia as a risk for falls among community-dwelling older people and nursing home older persons. Prospective cohort studies that evaluated the association between sarcopenia and falls in older adults were identified via a systematic literature search of Medline (via Ovid), PubMed, EMBASE, and the Cochrane CENTRAL Library from database inception until October 15, 2018, in English and Chinese. 10 studies (10,073 participants) were included in the meta-analysis. Among older adults, having sarcopenia was significantly associated with a higher risk of falls, compared to older adults without sarcopenia (pooled OR-odds ratio = 1.52, 95% CI-confidence interval: 1.32–1.77, I2 = 39.1%). In addition, the results of subgroup analysis indicated that male participants with sarcopenia had a higher risk of falls than mixed gender participants with sarcopenia (pooled OR = 1.72, 95% CI: 1.36–2.18 versus pooled OR = 1.41, 95% CI: 1.16–1.70). Other subgroup analyses were conducted using different study follow-up periods (>1 year versus ≤ 1 year) (pooled OR 1.63, 95% CI: 1.38–1.92 versus 1.20, 95% CI: 0.87–1.65). In addition, community-dwelling older people with sarcopenia was significantly increase risk of fall, compared with non-sarcopenia (pooled OR = 1.69, 95% CI: 1.43–2.00), whereas it was not found among nursing home residents (pooled OR = 1.12, 95% CI: 0.84–1.51). Furthermore, sarcopenia definition subgroup analysis found that older adults with sarcopenia increase the risk of falls when using EWGSOP (pooled OR = 1.43, 95% CI: 1.19–1.72), FNIH (pooled OR = 1.82, 95% CI: 1.39–2.37), AWGS (pooled OR = 7.68, 95% CI: 1.41–41.80), respectively. The present study found that sarcopenia is a risk factor for falls among community-dwelling older people, but not among nursing home older persons. Future research is needed to provide evidence for specific interventions aimed at treating sarcopenia and preventing falls among older adults dwelling in the community. • Meta-analysis found that sarcopenia is a risk factor for falls among community-dwelling older adults. (OR = 1.52, CI: 1.32–1.77). [ABSTRACT FROM AUTHOR]

DNA damage caused by $\gamma $ -irradiation initiates oscillatory expression of the p53 genetic network. Although many studies revealed the effects of the p53-Mdm2 circuit on p53 dynamics, a few studies explored the contribution of upstream kinases to p53 oscillation. In this paper, an integrated mathematical model of the p53 network in response to $\gamma $ -irradiation is studied, which consists of five basic components, two ubiquitous time delays, and two negative feedback loops. It is found that recurrent p53 pulses are externally initiated by ataxia telangiectasia mutated (ATM), and the negative feedback loop formed between ATM and p53, via Wip1, plays a dominant role in generating p53 oscillation. In addition, p53 oscillation requires not only an appropriate Mdm2 negative strength but also a threshold level of Wip1 negative strength. Furthermore, the time delays required for transcription and translation of Mdm2 and Wip1 proteins are essential for p53 oscillation. In particular, the critical value of time delay for inducing oscillation and the properties of delay-driven Hopf bifurcation are theoretically analyzed. As expected, the results are clearly in consistence with biological experiments and observations. [ABSTRACT FROM AUTHOR]

Although the oscillatory dynamics of the p53 network have been extensively studied, the understanding of the mechanism of delay‐induced oscillations is still limited. In this paper, a comprehensive mathematical model of p53 network is studied, which contains two delayed negative feedback loops. By studying the model with and without explicit delays, the results indicate that the time delay of Mdm2 protein synthesis can well control the pulse shape but cannot induce p53 oscillation alone, while the time delay required for Wip1 protein synthesis induces a Hopf bifurcation to drive p53 oscillation. In addition, the synergy of the two delays will cause the p53 network to oscillate in advance, indicating that p53 begins the repair process earlier in the damaged cell. Furthermore, the stability and bifurcation of the model are addressed, which may highlight the role of time delay in p53 oscillations. [ABSTRACT FROM AUTHOR]

In this paper, a delayed mathematical model was developed based on experimental data to understand how the time delays required for transcription and translation in Mdm2 gene expression affect the kinetic behavior of the p53-Mdm2 network. Taking the time delays as the main research parameters, the stability of the system at the positive equilibrium was studied by using the theoretical method of delay differential equation. We found that such delays can induce oscillations by undergoing a supercritical Hopf bifurcation. Then, we used the normal form theory and the center manifold reduction to study the direction and stability of the bifurcation in detail. Furthermore, we also studied the effects of the length of time delays and the model parameters by numerical simulations. We found that time delays in Mdm2 synthesis are required for p53 oscillations and the length of such delays can determine the amplitude and period of the oscillations. In addition, the model parameters can also change the stability of the system. These results illustrate that the repair process after DNA damage can be regulated by varying time delays and the model parameters. [ABSTRACT FROM AUTHOR]

Circadian rhythm disruptions are linked to increased cancer risk and unfavorable prognosis in patients with cancer, highlighting the critical role of the interplay between the circadian rhythm factor Per2 and the tumor suppressor p53. This brief presents, for the first time, a mathematical model to capture the dynamics of the p53-Per2 network in DNA-damaged cells. The model accurately describes the different stages of the process from unstressed cells to cellular repair and finally to apoptosis as the degree of DNA damage increases. Furthermore, it is found that increasing the inhibition of Per2 by p53 leads to the phase advance of Per2 oscillations, whereas by modulating the inhibition of Mdm2 by Per2, an independent amplitude modulation of active p53 can be achieved, with the range of modulation increasing with the strength of the inhibition. Moreover, the effects of time delays inherent in the transcription, translation, and nuclear translocation of Per2 on the circadian rhythm of DNA-damaged cells are quantitatively investigated by theoretical analyses. It is found that time delays can induce stable oscillations through a supercritical Hopf bifurcation, thereby maintaining the circadian function of DNA-damaged cells and enhancing their DNA-damage repair capacity. This study proposes new insights into cancer prevention and treatment strategies.

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objectives: This study aims to review the evidence of sarcopenia as a predictor of all-cause mortality among nursing home residents., Design: Systematic review and meta-analysis of observational cohort studies., Data Sources: PubMed, EMBASE and the Cochrane Library databases were searched for relevant articles., Participants: Nursing home residents., Primary and Secondary Outcome Measures: All-cause mortality., Data Analysis: Summary-adjusted HRs or risk ratios (RRs) were calculated by fixed-effects model. The risk of bias was assessed by Newcastle-Ottawa Scale., Results: Of 2292 studies identified through the systematic review, six studies (1494 participants) were included in the meta-analysis. Sarcopenia was significantly associated with a higher risk for all-cause mortality among nursing home residents (pooled HR 1.86, 95% CI 1.42 to 2.45, p<0.001, I 2 =0). In addition, the subgroup analysis demonstrated that sarcopenia was associated with all-cause mortality (pooled HR 1.87,95% CI 1.38 to 2.52, p<0.001) when studies with a follow-up period of 1 year or more were analysed; however, this was not found for studies with the follow-up period less than 1 year. Furthermore, sarcopenia was significantly associated with the risk of mortality among older nursing home residents when using bioelectrical impedance analysis to diagnosis muscle mass (pooled HR 1.88, 95% CI 1.39 to 2.53, p<0.001); whereas, it was not found when anthropometric measures were used to diagnosis muscle mass., Conclusion: Sarcopenia is a significant predictor of all-cause mortality among older nursing home residents. Therefore, it is important to diagnose and treat sarcopenia to reduce mortality rates among nursing home residents., Prospero Registration Number: CRD42018081668., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims and Objective: A large number of experimental evidences report that the oscillatory dynamics of p53 would regulate the cell fate decisions. Moreover, multiple time delays are ubiquitous in gene expression which have been demonstrated to lead to important consequences on dynamics of genetic networks. Although delay-driven sustained oscillation in p53-based networks is commonplace, the precise roles of such delays during the processes are not completely known., Method: Herein, an integrated model with five basic components and two time delays for the network is developed. Using such time delays as the bifurcation parameter, the existence of Hopf bifurcation is given by analyzing the relevant characteristic equations. Moreover, the effects of such time delays are studied and the expression levels of the main components of the system are compared when taking different parameters and time delays., Result and Conclusion: The above theoretical results indicated that the transcriptional and translational delays can induce oscillation by undergoing a super-critical Hopf bifurcation. More interestingly, the length of these delays can control the amplitude and period of the oscillation. Furthermore, a certain range of model parameter values is essential for oscillation. Finally, we illustrated the main results in detail through numerical simulations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Cyclophilin A (CypA) is implicated in rheumatoid arthritis (RA) pathogenesis. We studied whether a novel anti-CypA single domain antibody (sdAb) treatment would modulate the severity of the disease in two different animal models of RA., Methods: A novel sdAb, named sdAbA1, was screened from an immunized camel sdAb library and found to have a high binding affinity (KD = 6.9 × 10-9 M) for CypA. The SCID-HuRAg model and the collagen-induced arthritis (CIA) in mice were used to evaluate the effects of sdAbA1 treatment on inflammation and joint destruction. For in vitro analysis, monocytes/macrophages were purified from synovial fluid and peripheral blood of patients with RA and were tested for the effect of anti-CypA sdAb on metalloproteinase (MMP) production. Human monocyte cell line THP-1 cells were selected and western blot analyses were performed to examine the potential signaling pathways., Results: In the CIA model of RA, the sdAbA1 treatment resulted in a significant decrease in clinical symptoms as well as of joint damage (P <0.05). In the SCID-HuRAg model, treatment with anti-CypA antibody sdAbA1 significantly reduced cartilage erosion, inflammatory cell numbers and MMP-9 production in the implanted tissues (P <0.05). It also significantly reduced the levels of human inflammatory cytokines IL-6 and IL-8 in mouse serum (P <0.05). No toxic effects were observed in the two animal models. In vitro results showed that sdAbA1 could counteract CypA-dependent MMP-9 secretion and IL-8 production by interfering with the ERK-NF-κB pathway., Conclusions: Blockade of CypA significantly inhibited synovitis and cartilage/bone erosion in the two tested animal models of RA. Our findings provide evidence that sdAbA1 may be a potential therapeutic agent for RA.