Imperfect and Bogdanov-Takens bifurcations in biological models: from harvesting of species to isolation of infectives.

A natural biological system under human interventions may exhibit complex dynamical behaviors which could lead to either the collapse or stabilization of the system. The bifurcation theory plays an important role in understanding this evolution process by modeling and analyzing the biological system. In this paper, we examine two types of biological models that Fred Brauer made pioneer contributions: predator-prey models with stocking/harvesting and epidemic models with importation/isolation. First we consider the predator-prey model with Holling type II functional response whose dynamics and bifurcations are well-understood. By considering human interventions such as constant harvesting or stocking of predators, we show that the system under human interventions undergoes imperfect bifurcation and Bogdanov-Takens bifurcation, which induces much richer dynamical behaviors such as the existence of limit cycles or homoclinic loops. Then we consider an epidemic model with constant importation/isolation of infective individuals and observe similar imperfect and Bogdanov-Takens bifurcations when the constant importation/isolation rate varies.

Exploring the situational motivation of medical students through clinical medicine level test: a cross-sectional study.

China's Clinical Medicine Level Test (CMLT) was designed to evaluate the key factors that affect the learning outcome of medical students prior to entering clinical practice. In this study, we systemically analyzed the performance of a cohort of medical students at Jinan University School of Medicine participating in the recent CMLT. The analytical results of the medical students' written and objective structured clinical examination (OSCE) scores showed that their academic performance was predominantly associated with students' internship allocations, although other demographic characteristics such as sex, age, geographical origin of students, and grade point average (GPA) might be sporadically related to the students' OSCE performance at different OSCE stations. To explore the inherent reasons behind this, a survey was implemented among the medical students who participated in the examination to further interpret the factors influencing the students' learning outcome. The findings of this questionnaire manifested that intrinsic motivation and identified regulation acted as the major motivational profiles for the medical students from three different internship sites, whereas external regulation emerged as the crucial factor to make the students perform well academically in the CMLT. The result of this study suggested that strengthening the quality control of the clinical learning environment and improving medical administration may still be the most effective approaches to ensure the quality of clinical medical education.

Plantamajoside inhibits high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in rat glomerular mesangial cells through the inactivation of Akt/NF-κB pathway.

Plantamajoside (PMS) is a phenylpropanoid glycoside that possesses anti-diabetic activity. However, the effect of PMS on diabetic nephropathy (DN) has not been investigated. This study aimed to evaluate the role of PMS in DN and the potential mechanism. The rat glomerular mesangial cells ((MCs) (HBZY-1 cells) were cultured under high glucose (HG) condition or normal condition with or without the treatment of PMS. The results showed that PMS ameliorated the cell injury that was induced by HG in HBZY-1 cells. The HG-caused increases in reactive oxygen species (ROS) and malondialdehyde (MDA) production and decrease in superoxide dismutase (SOD) activity were prevented by PMS. The qRT-PCR and ELISA assays demonstrated an anti-inflammatory activity of PMS, as evidenced by decreased levels of TNF-α, IL-1ß, and IL-6 in HG-induced HBZY-1 cells. Moreover, the increased levels of fibronectin (FN) and collagen type IV (Col IV) in HBZY-1 cells caused by HG were also reduced by PMS treatment. Furthermore, PMS significantly suppressed HG-induced activation of Akt/NF-κB signaling in HBZY-1 cells. Taken together, these findings indicated that PMS alleviated HG-induced injury in HBZY-1 cells through suppressing oxidative stress, inflammatory response, and extracellular matrix (ECM) accumulation via the inactivating Akt/NF-κB pathway. Thus, PMS might possess potential capacity for the treatment of DN.

The clinical value of hematological markers in rheumatoid arthritis patients treated with tocilizumab.

BACKGROUND: Emerging evidence indicates that some hematological markers have critical value in evaluating treatment response. This study was performed to determine the clinical value of hemoglobin (Hb), platelet (Plt), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ). METHODS: Fifty-two RA patients receiving TCZ were recruited and followed for 6 months. The values of abovementioned hematological markers were collected. Clinical disease activity index (CDAI) and disease activity score based on 28 joints (DAS28)-ESR were calculated. Correlation analysis was conducted by calculating Pearson's correlation coefficient. The change in disease activity between groups according to the baseline level of hematological markers was compared by t test. RESULTS: Significant correlation between change in NLR (△NLR), change in PLR (△PLR), and change in CDAI (△CDAI) was found (△NLR: r = 0.30, P = 0.03; △PLR: r = 0.31, P = 0.03). The change in Plt (△Plt) was correlated with change in DAS28-ESR (△DAS28-ESR) (r = 0.36, P = 8.24 × 10-3 ). Greater improvement in CDAI was seen in patients categorized into Plt high group (t = 2.06, P = 0.04), NLR high group (t = 2.15, P = 0.04), and PLR high group (t = 2.41, P = 0.02) compared with the contrast group. CONCLUSION: Our study demonstrated that △Plt, △NLR, and △PLR could be used to monitor the clinical response to TCZ. RA patients with high baseline levels of Plt, NLR, and PLR achieved more improvement, indicating these hematological markers might be utilized to guide TCZ treatment.

The existence of periodic orbits and invariant tori for some 3-dimensional quadratic systems.

We use the normal form theory, averaging method, and integral manifold theorem to study the existence of limit cycles in Lotka-Volterra systems and the existence of invariant tori in quadratic systems in ℝ(3).

Multiparametric bifurcations of an epidemiological model with strong Allee effect.

In this paper we completely study bifurcations of an epidemic model with five parameters introduced by Hilker et al. (Am Nat 173:72-88, 2009), which describes the joint interplay of a strong Allee effect and infectious diseases in a single population. Existence of multiple positive equilibria and all kinds of bifurcation are examined as well as related dynamical behavior. It is shown that the model undergoes a series of bifurcations such as saddle-node bifurcation, pitchfork bifurcation, Bogdanov-Takens bifurcation, degenerate Hopf bifurcation of codimension two and degenerate elliptic type Bogdanov-Takens bifurcation of codimension three. Respective bifurcation surfaces in five-dimensional parameter spaces and related dynamical behavior are obtained. These theoretical conclusions confirm their numerical simulations and conjectures by Hilker et al., and reveal some new bifurcation phenomena which are not observed in Hilker et al. (Am Nat 173:72-88, 2009). The rich and complicated dynamics exhibit that the model is very sensitive to parameter perturbations, which has important implications for disease control of endangered species.

Magnetic resonance imaging for prostate cancer clinical application.

As prostate cancer is a biologically heterogeneous disease for which a variety of treatment options are available, the major objective of prostate cancer imaging is to achieve more precise disease characterization. In clinical practice, magnetic resonance imaging (MRI) is one of the imaging tools for the evaluation of prostate cancer, the fusion of MRI or dynamic contrast-enhanced MRI (DCE-MRI) with magnetic resonance spectroscopic imaging (MRSI) is improving the evaluation of cancer location, size, and extent, while providing an indication of tumor aggressiveness. This review summarizes the role of MRI in the application of prostate cancer and describes molecular MRI techniques (including MRSI and DCE-MRI) for aiding prostate cancer management.

Network analysis of eating disorder and depression symptoms among university students in the late stage of COVID-19 pandemic in China.

Background: Eating disorders (EDs) and depression are common in university students, especially during the COVID-19 pandemic. The aim of this study was to elucidate characteristics of EDs and depression symptoms networks among Chinese university students in the later stage of the COVID-19 pandemic in China. Methods: A total of 929 university students completed the SCOFF questionnaire measuring EDs and Patient Health Questionnaire with 9 items (PHQ-9) measuring depression in Guangzhou, China. The network model was applied to identify central symptoms, bridge symptoms, and important connections between SCOFF and PHQ-9 using R studio. The subgroup analyses of both genders in medical and non-medical students were further explored. Results: In the networks of the whole sample, central symptoms included "Loss of control over eating" (EDs) and "Appetite changes" (depression). The bridge connections were between "Loss of control over eating" (EDs) and "Appetite changes" (depression), between "Deliberate vomiting" (EDs) and "Thoughts of death" (depression). "Appetite changes" (depression) and "Feeling of worthlessness" (depression) were central symptoms in both subgroups of medical and non-medical students. "Fatigue" (depression) was the central symptom in the female and medical students group. The edge between "Loss of control over eating" (EDs) and "Appetite changes" (depression) acted as a bridge in all subgroups. Conclusion: Social network approaches offered promising ways of further understanding the association between EDs and depression among university students during the pandemic of COVID-19 in China. Investigations targeting central and bridge symptoms would help to develop effective treatments for both EDs and depression for this population.

Gadobenate dimeglumine-enhanced liver magnetic resonance imaging: value of hepatobiliary phase for the detection of focal liver lesions.

OBJECTIVE: The objective of the study was to determine the value of addition of hepatobiliary phase to dynamic gadobenate dimeglumine (Gd-BOPTA)-enhanced imaging for the detection of focal liver lesions (nodules with diameter ≤3.0 cm). METHODS: Routine nonenhanced magnetic resonance images were obtained in 25 patients with focal liver lesions suggested by ultrasonography and/or computed tomography.T1-weighted dynamic gradient-echo images were acquired immediately and 100 minutes after bolus injection of Gd-BOPTA. The number of the lesions detected by T1-weighted imaging, T2-weighted imaging, diffusion-weighted imaging, dynamic contrast-enhanced, and delayed hepatobiliary-phase imaging was counted, respectively. Contrast-to-noise ratios were measured for all the sequences including delayed hepatobiliary-phase imaging. The signal intensity and morphologic features of liver parenchyma and lesions were recorded and analyzed. RESULTS: There were 7 patients with hepatocellular carcinomas, 6 with hemangiomas, 7 with metastases, and 5 with cholangiocarcinomas. The delayed hepatobiliary-phase imaging showed a homogeneous enhancement of liver parenchyma and distinctive enhancement features of focal liver lesions. The delayed hepatobiliary-phase imaging was better than diffusion-weighted imaging for the detection of focal liver lesions (P < 0.05). CONCLUSION: The addition of hepatobiliary-phase imaging to Gd-BOPTA-enhanced dynamic imaging increased the sensitivity and accuracy for the detection of focal hepatic lesions.

Assessment of genetic polymorphisms within nuclear factor-κB signaling pathway genes in rheumatoid arthritis: Evidence for replication and genetic interaction.

OBJECTIVE: This study was performed to replicate the associations of genetic polymorphisms within nuclear factor-κB (NF-κB) signaling pathway genes with rheumatoid arthritis (RA), and to further examine genetic interactions in a Chinese population. METHODS: A total of eleven single-nucleotide polymorphisms (SNPs) were genotyped in 594 RA patients and 604 healthy controls. RESULTS: Genetic association analysis revealed that NFKBIE rs2233434, TNIP1 rs10036748 and BLK rs13277113 were significantly associated with RA, cyclic citrullinated peptide (CCP)-positive RA and rheumatoid factor (RF)-positive RA, and TNFAIP3 rs2230926 was significantly associated with CCP-positive RA. Significant additive interaction was observed between NFKB1 rs28362491 and IKBKE rs12142086 (RERI = 0.76, 95% CI 0.13-1.38; AP = 0.57, 95% CI 0.11-1.03), NFKBIE rs2233434 and BLK rs13277113 (RERI = 1.41, 95% CI 0.88-1.94; AP = 0.85, 95% CI 0.50-1.20), NFKBIL rs2071592 and TNIP1 rs10036748 (RERI = 0.59, 95% CI 0.17-1.02; AP = 0.46, 95% CI 0.05-0.87), UBE2L3 rs5754217 and TNFSF4 rs2205960 (RERI = 0.50, 95% CI 0.16-0.84; AP = 0.57, 95% CI 0.09-1.05). Significant multiplicative interaction was detected between BLK rs13277113 and UBE2L3 rs5754217 (p = 0.02), BLK rs13277113 and TNFSF4 rs2205960 (p = 0.03). CONCLUSIONS: Our results lent further support to the role of NF-κB signaling pathway in the pathogenesis of RA from a genetic perspective.

The Dolaflexin-based Antibody-Drug Conjugate XMT-1536 Targets the Solid Tumor Lineage Antigen SLC34A2/NaPi2b.

Target selection for antibody-drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10-15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.

An intra-host mathematical model on interaction between HIV and malaria.

In this paper a mathematical model is proposed for the interaction of the immune system with HIV viruses and malaria parasites in an individual host. It consists of a system of three coupled ordinary differential equations, which represents the rate of change in the concentration of malaria parasites, HIV viruses and immunity effector within a host, respectively. The theoretical model gives insight into the biological balance between pathogen replication and the immune response to the pathogen: persistence versus elimination of the pathogen, which determines the outcome of infection. Dynamical analysis shows that the outcomes of the interactions between the immune system of the host with either malaria parasites or HIV viruses are dramatic such as malaria infection promoting proliferation of HIV virus, HIV infection increasing the risk from malaria and the immune system of the host failing to keep the diseases under control, etc. The results provide a new perspective for understanding of the complexity mechanisms of the co-infection (or dual infection) with malaria and HIV in a host.

Transcription factor YY1 expression in human gastrointestinal cancer cells.

Over-expression of the multifunctional zinc-finger transcription factor Yin Yang 1 (YY1) has been associated with cellular proliferation and resistance to apoptotic stimuli. In this study, we report that YY1 was uniformly highly over-expressed in a wide range of human cancer cell lines and in human colon cancer tissue samples. The examination of YY1-specific mRNA expression demonstrated at least six mRNA isoforms ubiquitously expressed in normal human adult and fetal tissues. Substantial over-expression of two specific mRNA isoforms of 7.5 and 2.9 kb size, respectively, was detected in gastrointestinal and other cancer cells in vitro, whereby mRNA stability differed significantly between various cell lines. YY1 protein expression levels were similar in different colon cancer cell lines. Using FISH analysis of several colorectal cancer cell lines, the human YY1 locus was expectedly identified on chromosome 14q32 and no evidence of gene amplification and chromosomal translocation was observed. However, varying degree of aneuploidy was noted in vitro. YY1 immunoreactivity in human colon tumor samples was found more intense in poorly differentiated tumors than in moderately and well differentiated colon cancers and lower expression levels tended to be associated with shorter survival. In conclusion, YY1 was over-expressed in colon cancer in the absence of gene amplification and chromosomal translocation. YY1 mRNA and protein stability are important regulatory mechanisms of YY1 expression in colon cancer.

Body Mass Index and Clinical Response to Tocilizumab in Patients With Rheumatoid Arthritis.

OBJECTIVES: This study aims to determine whether baseline body mass index (BMI) affects clinical response to tocilizumab (TCZ) after six months of treatment in rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: In this prospective study, a total of 52 RA patients (10 males, 42 females; mean age 50.6±12.2 years; range, 23 to 73 years) receiving intravenous TCZ were consecutively recruited and followed-up for six months. BMI was calculated before initiation of TCZ treatment. The primary clinical response criterion was clinical disease activity index (CDAI) low disease activity (LDA) and the secondary clinical response criteria included CDAI remission, disease activity score based on 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) LDA, DAS28-ESR remission, European League Against Rheumatism (EULAR) good response, and decreased DAS28-ESR (ΔDAS28-ESR)≥1.2. RESULTS: The number of RA patients classified as normal weight, overweight, and obese according to baseline BMI was 38 (73.1%), eight (15.4%), and six (11.5%), respectively. Similar baseline BMI median levels were found between RA patients reaching CDAI LDA and non-LDA: 21.11 (18.94-23.72) versus 20.78 (20.03-22.29) (p=0.98), and non-significant difference in the proportion of responders between normal weight and overweight/obese RA patients was found (p=0.47). No significant difference was found when the secondary clinical response criteria were applied. CONCLUSION: Our study demonstrates that BMI is not associated with clinical response to TCZ among RA patients and TCZ may be used to treat RA patients regardless of BMI levels.

Cobalt metal-mixed organic complex-based hybrid micromaterials: ratiometric detection of cyanide.

A micrometer-sized hybrid crystalline material was facilely fabricated from the synergistic coordination chemistry of two types of 2-hydroxyazobenzene building blocks and cobalt ions. This hybrid crystalline material functioned as both receptor and signal reporter in cyanide (CN-) sensing with ratiometric absorption responses at 456 nm and 537 nm. The mechanism of CN- sensing involves partial ligand dissociation accompanied by the formation of a new organic metal-CN- adduct. We believe that this protocol would be valuable in achieving the expected selectivities and sensitivities for a wide variety of analytes in many chemical and biological systems in the future.

Global analysis of an epidemic model with nonmonotone incidence rate.

In this paper we study an epidemic model with nonmonotonic incidence rate, which describes the psychological effect of certain serious diseases on the community when the number of infectives is getting larger. By carrying out a global analysis of the model and studying the stability of the disease-free equilibrium and the endemic equilibrium, we show that either the number of infective individuals tends to zero as time evolves or the disease persists.

Bifurcations of an epidemic model with non-monotonic incidence rate of saturated mass action.

In this paper, we study the bifurcations of an epidemic model with non-monotonic incidence rate of saturated mass action, which describes the psychological effects of the community on certain serious diseases when the number of infective is getting larger. By carrying out the bifurcation analysis of the model, we show that there exist some values of the model parameters such that numerous kinds of bifurcation occur for the model, such as Hopf bifurcation, Bogdanov-Takens bifurcation.

Bombesin regulates cyclin D1 expression through the early growth response protein Egr-1 in prostate cancer cells.

Our previous studies indicate that the activation of mitogen-activated protein kinase (MAPK) pathway is involved in bombesin-induced cell proliferation in prostate cancer cells. Cyclin D1 is a critical regulator involved in cell cycle progression through the G1 phase into the S phase, thereby contributing to cell proliferation. Mostly, mitogen-stimulated expression of cyclin D1 is attributed to the extracellular signal-regulated kinase (ERK) activation. Here, we found that bombesin induced human cyclin D1 expression on both mRNA and protein levels in DU-145 prostate cancer cells. Mutational analyses showed that bombesin-enhanced cyclin D1 transcription required the binding of nuclear proteins to the -143 to -105 region of the human cyclin D1 promoter, which contains binding sites for transcription factors Sp-1 and early growth response protein (Egr-1). Do novo protein synthesis was requisite for bombesin-induced cyclin D1 expression. Further studies showed Egr-1 was induced upon bombesin stimulation. The induction of Egr-1 expression and its binding to the cyclin D1 promoter were essential for bombesin-enhanced cyclin D1 transcription. Inhibition of MAPK pathway with either the MEK1 inhibitor PD98059 or a dominant-negative Ras mutant, RasN17, abolished bombesin-induced cyclin D1 activation. Taken together, bombesin-induced cyclin D1 expression in prostate cancer cells is mediated by Egr-1 activation and the interaction of Egr-1 with the Egr-1/Sp1 motif of the cyclin D1 promoter through the activation of MAPK pathway. These findings represent a novel mechanism of bombesin-dependent stimulation of mitogenesis by regulating directly the cell cycle in prostate cancer.

Global dynamics and bifurcation analysis of a host-parasitoid model with strong Allee effect.

In this paper, we study the global dynamics and bifurcations of a two-dimensional discrete time host-parasitoid model with strong Allee effect. The existence of fixed points and their stability are analysed in all allowed parametric region. The bifurcation analysis shows that the model can undergo fold bifurcation and Neimark-Sacker bifurcation. As the parameters vary in a small neighbourhood of the Neimark-Sacker bifurcation condition, the unique positive fixed point changes its stability and an invariant closed circle bifurcates from the positive fixed point. From the viewpoint of biology, the invariant closed curve corresponds to the periodic or quasi-periodic oscillations between host and parasitoid populations. Furthermore, it is proved that all solutions of this model are bounded, and there exist some values of the parameters such that the model has a global attractor. These theoretical results reveal the complex dynamics of the present model.

Dynamics of epidemic models with asymptomatic infection and seasonal succession.

In this paper, we consider a compartmental SIRS epidemic model with asymptomatic infection and seasonal succession, which is a periodic discontinuous differential system. The basic reproduction number R0 is defined and evaluated directly for this model, and uniform persistence of the disease and threshold dynamics are obtained. Specially, global dynamics of the model without seasonal force are studied. It is shown that the model has only a disease-free equilibrium which is globally stable if R0 ≤ 1, and as R0 > 1 the disease-free equilibrium is unstable and there is an endemic equilibrium, which is globally stable if the recovering rates of asymptomatic infectives and symptomatic infectives are close. These theoretical results provide an intuitive basis for understanding that the asymptomatically infective individuals and the seasonal disease transmission promote the evolution of the epidemic, which allow us to predict the outcomes of control strategies during the course of the epidemic.