scholarly journals Multiscale computational modeling of cancer growth using features derived from microCT images

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. Hossein Zangooei ◽  
Ryan Margolis ◽  
Kenneth Hoyt
Keyword(s):  
Computational Model ◽  
Initial Conditions ◽  
Growth Patterns ◽  
Computational Method ◽  
Rectangular Lattice ◽  
Microvascular Network ◽  
Network Growth ◽  
Experimental Findings ◽  
The Impact

AbstractAdvances in medical imaging technologies now allow noninvasive image acquisition from individual patients at high spatiotemporal resolutions. A relatively new effort of predictive oncology is to develop a paradigm for forecasting the future status of an individual tumor given initial conditions and an appropriate mathematical model. The objective of this study was to introduce a comprehensive multiscale computational method to predict cancer and microvascular network growth patterns. A rectangular lattice-based model was designed so different evolutionary scenarios could be simulated and for predicting the impact of diffusible factors on tumor morphology and size. Further, the model allows prediction-based simulation of cell and microvascular behavior. Like a single cell, each agent is fully realized within the model and interactions are governed in part by machine learning methods. This multiscale computational model was developed and incorporated input information from in vivo microscale computed tomography (microCT) images acquired from breast cancer-bearing mice. It was found that as the difference between expansion of the cancer cell population and microvascular network increases, cells undergo proliferation and migration with a greater probability compared to other phenotypes. Overall, multiscale computational model agreed with both theoretical expectations and experimental findings (microCT images) not used during model training.

scholarly journals fuNTRp: Identifying protein positions for variation driven functional tuning

2019 ◽  
Author(s):  
Maximilian Miller ◽  
Daniel Vitale ◽  
Peter Kahn ◽  
Burkhard Rost ◽  
Yana Bromberg
Keyword(s):  
Protein Design ◽  
Computational Method ◽  
Protein Activity ◽  
Protein Functions ◽  
Disease Associations ◽  
Position Type ◽  
Variant Effect ◽  
Evolution Understanding ◽  
The Impact

ABSTRACTEvaluating the impact of non-synonymous genetic variants is essential for uncovering disease associations and mechanisms of evolution. Understanding corresponding sequence changes is also fundamental for synthetic protein design and stability assessments. However, the performance gain of variant effect predictors observed in recent years is not in line with the increased complexity of new methods. One likely reason for this might be that most approaches use similar sets of gene/protein features for modeling variant effect, often emphasizing sequence conservation. While high levels of conservation highlight residues essential for protein activity, much of the in vivo observable variation is arguably weaker in its impact and, thus, requires evaluation at a higher level of resolution. Here we describe function Neutral/Toggle/Rheostat predictor (funtrp), a novel computational method that categorizes protein positions based on the position-specific expected range of mutational impacts: Neutral (weak/no effects), Rheostat (function-tuning positions), or Toggle (on/off switches). We show that position types do not correlate strongly with familiar protein features such as conservation or protein disorder. We also find that position type distribution varies across different protein functions. Finally, we demonstrate that position types reflect experimentally determined functional effects and can thus improve performance of existing variant effect predictors and suggest a way forward for the development of new ones.

scholarly journals funtrp: identifying protein positions for variation driven functional tuning

2019 ◽  
Vol 47 (21) ◽  
pp. e142-e142 ◽  
Author(s):  
Maximilian Miller ◽  
Daniel Vitale ◽  
Peter C Kahn ◽  
Burkhard Rost ◽  
Yana Bromberg
Keyword(s):  
Protein Design ◽  
Computational Method ◽  
Protein Activity ◽  
Synthetic Protein ◽  
Protein Functions ◽  
Disease Associations ◽  
Position Type ◽  
Variant Effect ◽  
The Impact

Abstract Evaluating the impact of non-synonymous genetic variants is essential for uncovering disease associations and mechanisms of evolution. An in-depth understanding of sequence changes is also fundamental for synthetic protein design and stability assessments. However, the variant effect predictor performance gain observed in recent years has not kept up with the increased complexity of new methods. One likely reason for this might be that most approaches use similar sets of gene and protein features for modeling variant effects, often emphasizing sequence conservation. While high levels of conservation highlight residues essential for protein activity, much of the variation observable in vivo is arguably weaker in its impact, thus requiring evaluation at a higher level of resolution. Here, we describe functionNeutral/Toggle/Rheostatpredictor (funtrp), a novel computational method that categorizes protein positions based on the position-specific expected range of mutational impacts: Neutral (weak/no effects), Rheostat (function-tuning positions), or Toggle (on/off switches). We show that position types do not correlate strongly with familiar protein features such as conservation or protein disorder. We also find that position type distribution varies across different protein functions. Finally, we demonstrate that position types can improve performance of existing variant effect predictors and suggest a way forward for the development of new ones.

Experimental Study of the Impact of Alisma plantago-aquatica Secretions on Pathogenic Bacteria

2014 ◽  
Vol 1 (3) ◽  
pp. 3-7
Author(s):  
O. Zhukorskyy ◽  
O. Hulay
Keyword(s):  
Pathogenic Bacteria ◽  
Initial Density ◽  
Biologically Active ◽  
Erysipelothrix Rhusiopathiae ◽  
Natural Focus ◽  
Test Species ◽  
Popula Tions ◽  
And Control ◽  
The Impact

Aim. To estimate the impact of in vivo secretions of water plantain (Alisma plantago-aquatica) on the popula- tions of pathogenic bacteria Erysipelothrix rhusiopathiae. Methods. The plants were isolated from their natural conditions, the roots were washed from the substrate residues and cultivated in laboratory conditions for 10 days to heal the damage. Then the water was changed; seven days later the selected samples were sterilized using fi lters with 0.2 μm pore diameter. The dilution of water plantain root diffusates in the experimental samples was 1:10–1:10,000. The initial density of E. rhusiopathiae bacteria populations was the same for both experimental and control samples. The estimation of the results was conducted 48 hours later. Results. When the dilution of root diffusates was 1:10, the density of erysipelothrixes in the experimental samples was 11.26 times higher than that of the control, on average, the dilution of 1:100 − 6.16 times higher, 1:1000 – 3.22 times higher, 1:10,000 – 1.81 times higher, respectively. Conclusions. The plants of A. plantago-aquatica species are capable of affecting the populations of E. rhusiopathiae pathogenic bacteria via the secretion of biologically active substances into the environment. The consequences of this interaction are positive for the abovementioned bacteria, which is demon- strated by the increase in the density of their populations in the experiment compared to the control. The intensity of the stimulating effect on the populations of E. rhusiopathiae in the root diffusates of A. plantago-aquatica is re- ciprocally dependent on the degree of their dilution. The investigated impact of water plantain on erysipelothrixes should be related to the topical type of biocenotic connections, the formation of which between the test species in the ecosystems might promote maintaining the potential of natural focus of rabies. Keywords: Alisma plantago-aquatica, in vivo secretions, Erysipelothrix rhusiopathiae, population density, topical type of connections.

Curcumin-containing Silver Nanoparticles prevent carbon tetrachlorideinduced hepatotoxicity in mice

2020 ◽  
Vol 23 ◽  
Author(s):  
Hossam Ebaid ◽  
Mohamed Habila ◽  
Iftekhar Hassan ◽  
Jameel Al-Tamimi ◽  
Mohamed S. Omar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Silver Nanoparticles ◽  
Nuclear Dna ◽  
Liquid Paraffin ◽  
Tail Length ◽  
Hepatic Tissue ◽  
Tissue Destruction ◽  
Group 2 ◽  
The Impact

Background: Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results: Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion: Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

2013 ◽  
Vol 150 (3) ◽  
pp. 1024-1031 ◽  
Author(s):  
Mohammad Hossein Boskabady ◽  
Sakine Shahmohammadi Mehrjardi ◽  
Abadorrahim Rezaee ◽  
Houshang Rafatpanah ◽  
Sediqeh Jalali
Keyword(s):  
Zataria Multiflora ◽  
Th2 Cytokine ◽  
Ifn Γ ◽  
The Impact

scholarly journals On Kaufmann's theory of the impact of the pianoforte hammer

1920 ◽  
Vol 97 (682) ◽  
pp. 99-110 ◽  
Keyword(s):  
Initial Conditions ◽  
Practical Importance ◽  
Prima Facie ◽  
Point Of View ◽  
Infinite Length ◽  
Modes Of Vibration ◽  
Rigorous Treatment ◽  
The Subject ◽  
Set Up ◽  
The Impact

The theory of the vibrations of the pianoforte string put forward by Kaufmann in a well-known paper has figured prominently in recent discussions on the acoustics of this instrument. It proceeds on lines radically different from those adopted by Helmholtz in his classical treatment of the subject. While recognising that the elasticity of the pianoforte hammer is not a negligible factor, Kaufmann set out to simplify the mathematical analysis by ignoring its effect altogether, and treating the hammer as a particle possessing only inertia without spring. The motion of the string following the impact of the hammer is found from the initial conditions and from the functional solutions of the equation of wave-propagation on the string. On this basis he gave a rigorous treatment of two cases: (1) a particle impinging on a stretched string of infinite length, and (2) a particle impinging on the centre of a finite string, neither of which cases is of much interest from an acoustical point of view. The case of practical importance treated by him is that in which a particle impinges on the string near one end. For this case, he gave only an approximate theory from which the duration of contact, the motion of the point struck, and the form of the vibration-curves for various points of the string could be found. There can be no doubt of the importance of Kaufmann’s work, and it naturally becomes necessary to extend and revise his theory in various directions. In several respects, the theory awaits fuller development, especially as regards the harmonic analysis of the modes of vibration set up by impact, and the detailed discussion of the influence of the elasticity of the hammer and of varying velocities of impact. Apart from these points, the question arises whether the approximate method used by Kaufmann is sufficiently accurate for practical purposes, and whether it may be regarded as applicable when, as in the pianoforte, the point struck is distant one-eighth or one-ninth of the length of the string from one end. Kaufmann’s treatment is practically based on the assumption that the part of the string between the end and the point struck remains straight as long as the hammer and string remain in contact. Primâ facie , it is clear that this assumption would introduce error when the part of the string under reference is an appreciable fraction of the whole. For the effect of the impact would obviously be to excite the vibrations of this portion of the string, which continue so long as the hammer is in contact, and would also influence the mode of vibration of the string as a whole when the hammer loses contact. A mathematical theory which is not subject to this error, and which is applicable for any position of the striking point, thus seems called for.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

scholarly journals A Rational Numerical Method for Simulation of Drop-Impact Dynamics of Oleo-Pneumatic Landing Gear

2021 ◽  
Vol 11 (9) ◽  
pp. 4136
Author(s):  
Rosario Pecora
Keyword(s):  
Numerical Method ◽  
Initial Conditions ◽  
Impact Load ◽  
Numerical Models ◽  
Landing Gear ◽  
Design Stage ◽  
Impact Dynamics ◽  
State Variables ◽  
Adopted Model ◽  
The Impact

Oleo-pneumatic landing gear is a complex mechanical system conceived to efficiently absorb and dissipate an aircraft’s kinetic energy at touchdown, thus reducing the impact load and acceleration transmitted to the airframe. Due to its significant influence on ground loads, this system is generally designed in parallel with the main structural components of the aircraft, such as the fuselage and wings. Robust numerical models for simulating landing gear impact dynamics are essential from the preliminary design stage in order to properly assess aircraft configuration and structural arrangements. Finite element (FE) analysis is a viable solution for supporting the design. However, regarding the oleo-pneumatic struts, FE-based simulation may become unpractical, since detailed models are required to obtain reliable results. Moreover, FE models could not be very versatile for accommodating the many design updates that usually occur at the beginning of the landing gear project or during the layout optimization process. In this work, a numerical method for simulating oleo-pneumatic landing gear drop dynamics is presented. To effectively support both the preliminary and advanced design of landing gear units, the proposed simulation approach rationally balances the level of sophistication of the adopted model with the need for accurate results. Although based on a formulation assuming only four state variables for the description of landing gear dynamics, the approach successfully accounts for all the relevant forces that arise during the drop and their influence on landing gear motion. A set of intercommunicating routines was implemented in MATLAB® environment to integrate the dynamic impact equations, starting from user-defined initial conditions and general parameters related to the geometric and structural configuration of the landing gear. The tool was then used to simulate a drop test of a reference landing gear, and the obtained results were successfully validated against available experimental data.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals Baicalin Represses Type Three Secretion System of Pseudomonas aeruginosa through PQS System

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1497
Author(s):  
Pansong Zhang ◽  
Qiao Guo ◽  
Zhihua Wei ◽  
Qin Yang ◽  
Zisheng Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Mammalian Cells ◽  
Secretion System ◽  
Chinese Herbs ◽  
Infection Model ◽  
Lung Pathology ◽  
Promising Alternative ◽  
The Impact

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

Sign in / Sign up

Export Citation Format

Share Document