Mild Perturbations Research Articles

Field-Assisted Contact Line Motion in Thin Films.

The balance of intermolecular and surface forces plays a critical role in the transport phenomena near the contact line region of an extended meniscus in several technologically important processes. Externally applied fields can alter the equilibrium and stability of the meniscus with concomitant effects on its shape and spreading characteristics and may even lead to an oscillation. This feature article provides a detailed account of the present and past efforts in exploring the behavior of curved thin liquid films subjected to mild thermal perturbations, heat input, and electrical and magnetic fields for pure as well as colloidal suspensions, including the effects of particle charge and polarity. The shape-dependent intermolecular force field has been evaluated in situ by a nonobtrusive optical technique utilizing the interference phenomena and subsequent image processing. The critical role of disjoining pressure is identified along with the determination of the Hamaker constant. The spatial and temporal variations of the capillary forces are evaluated for the advancing and receding menisci. The Maxwell-stress-induced enhanced spreading during electrowetting, at relatively low voltages, and that due to the application of a magnetic field are discussed with respect to their distinctly different characteristics and application potentials. The use of the augmented Young-Laplace equation elicited additional insights into the fundamental physics for flow in ultrathin liquid films.

Assessing the impact of the 4CL enzyme complex on the robustness of monolignol biosynthesis using metabolic pathway analysis

Lignin is a polymer present in the secondary cell walls of all vascular plants. It is a known barrier to pulping and the extraction of high-energy sugars from cellulosic biomass. The challenge faced with predicting outcomes of transgenic plants with reduced lignin is due in part to the presence of unique protein-protein interactions that influence the regulation and metabolic flux in the pathway. Yet, it is unclear why certain plants have evolved to create these protein complexes. In this study, we use mathematical models to investigate the role that the protein complex, formed specifically between Ptr4CL3 and Ptr4CL5 enzymes, have on the monolignol biosynthesis pathway. The role of this Ptr4CL3-Ptr4CL5 enzyme complex on the steady state flux distribution was quantified by performing Monte Carlo simulations. The effect of this complex on the robustness and the homeostatic properties of the pathway were identified by performing sensitivity and stability analyses, respectively. Results from these robustness and stability analyses suggest that the monolignol biosynthetic pathway is resilient to mild perturbations in the presence of the Ptr4CL3-Ptr4CL5 complex. Specifically, the presence of Ptr4CL3-Ptr4CL5 complex increased the stability of the pathway by 22%. The robustness in the pathway is maintained due to the presence of multiple enzyme isoforms as well as the presence of alternative pathways resulting from the presence of the Ptr4CL3-Ptr4CL5 complex.

Plant toxins: alkaloids and their toxicities

Since ancient civilization, plants have been utilized in many aspects of life, especially in medicinal purposes due to the presence of distinctive secondary metabolites like alkaloids, phenolics and terpenoids. Among them, alkaloids represent a large group of secondary metabolites that have basic properties and comprise nitrogen atom within the heterocyclic ring. Plant synthesizes alkaloids to maintain their survivability under unfavorable conditions. Over 3000 years, indigenous people have been used alkaloid-containing plant extracts to treat several ailments such as fever, snakebite and insanity. However, despite significant benefits to humans and pharmaceutical industries, some of the plant alkaloids are categorized as main plant toxins due to their enormous structural diversity and various modes of actions. Humans and animals can be exposed to toxic alkaloids either through inhalation, swallowing or by direct contact, therefore leads to the specific mechanism that involves receptors, transporters, enzymes and genetic materials at specific cells and tissues, hence may cause hepatotoxic effects and musculoskeletal deformities. This review focuses on some of the plant alkaloids such as pyrrolizidine, tropane, piperidine and indolizidine, which can give various side effects on humans and animals such as itching, nausea, vomiting, mild gastrointestinal perturbation, psychosis, paralysis, teratogenicity, arrhythmias and sudden death.

Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency.

Nodal patterning without Lefty inhibitory feedback is functional but fragile.

Developmental signaling pathways often activate their own inhibitors. Such inhibitory feedback has been suggested to restrict the spatial and temporal extent of signaling or mitigate signaling fluctuations, but these models are difficult to rigorously test. Here, we determine whether the ability of the mesendoderm inducer Nodal to activate its inhibitor Lefty is required for development. We find that zebrafish lefty mutants exhibit excess Nodal signaling and increased specification of mesendoderm, resulting in embryonic lethality. Strikingly, development can be fully restored without feedback: Lethal patterning defects in lefty mutants can be rescued by ectopic expression of lefty far from its normal expression domain or by spatially and temporally uniform exposure to a Nodal inhibitor drug. While drug-treated mutants are less tolerant of mild perturbations to Nodal signaling levels than wild type embryos, they can develop into healthy adults. These results indicate that patterning without inhibitory feedback is functional but fragile.

Mild metabolic perturbations alter succinylation of mitochondrial proteins.

Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have 1,190 unique succinylation sites representing multiple metabolic pathways. Succinylation is sensitive to both increases and decreases of the NAD+ -dependent desuccinylase, SIRT5. Although the succinyl group for succinylation is derived from metabolism, the effects of systematic variation of metabolism on mitochondrial succinylation are not known. Changes in succinylation of mitochondrial proteins following variations in metabolism were compared against the mitochondrial redox state as estimated by the mitochondrial NAD+ /NADH ratio using fluorescent probes. The ratio was decreased by reduced glycolysis and/or glutathione depletion (iodoacetic acid; 2-deoxyglucose), depressed tricarboxylic acid cycle activity (carboxyethyl ester of succinyl phosphonate), and impairment of electron transport (antimycin) or ATP synthase (oligomycin), while uncouplers of oxidative phosphorylation (carbonyl cyanide m-chlorophenyl hydrazine or tyrphostin) increased the NAD+ /NADH ratio. All of the conditions decreased succinylation. In contrast, reducing the oxygen from 20% to 2.4% increased succinylation. The results demonstrate that succinylation varies with metabolic states, is not correlated to the mitochondrial NAD+ /NADH ratio, and may help coordinate the response to metabolic challenge.

Photoisomerization of ethyl ferulate: A solution phase transient absorption study

Ethyl ferulate (ethyl 4-hydroxy-3-methoxycinnamate) is currently used as a sunscreening agent in commercial sunscreen blends. Recent time-resolved gas-phase measurements have demonstrated that it possesses long-lived (>ns) electronic excited states, counterintuitive to what one might anticipate for an effective sunscreening agent. In the present work, the photodynamics of ethyl ferulate in cyclohexane, are explored using time-resolved transient electronic absorption spectroscopy, upon photoexcitation to the 11ππ∗ and 21ππ∗ states. We demonstrate that ethyl ferulate undergoes efficient non-radiative decay to repopulate the electronic ground state, mediated by trans-cis isomerization. These results strongly suggest that even mild perturbations induced by a non-polar solvent, as may be found in a closer-to-market sunscreen blend, may contribute to our understanding of ethyl ferulate’s role as a sunscreening agent.

Transport of nanoparticles across pulmonary surfactant monolayer: a molecular dynamics study.

Pulmonary nanodrug delivery is an emerging concept, especially for targeted lung cancer therapy. Once inhaled, the nanoparticles (NPs) acting as drug carriers need to efficiently cross the pulmonary surfactant monolayer (PSM) of lung alveoli, which act as the first barrier for external particles entering the lung. Herein, by performing molecular dynamics simulations, we study how inhaled NPs interact with the PSM, particularly focusing on the transport of NPs with different properties across the PSM. While hydrophilic NPs translocate directly across the PSM, transport of hydrophobic NPs is achieved as the PSM wraps them. Intriguingly, when hydrophilic NPs are decorated with lipid molecules (LCNPs), they are wrapped by the PSM efficiently with mild PSM perturbation. Moreover, the structure formed is like a vesicle, which will likely fuse with cell membranes to accomplish the transport of hydrophilic NPs into secondary organs. This behavior makes the LCNP a prospective candidate for pulmonary nanodrug delivery. Herein, the effects of the physical properties of LCNPs on their transport are investigated. Increasing the LCNP size promotes its wrapping by reducing the PSM bending energy. The binding energy that drives transport can be strengthened by increasing the lipid coating density and the lipid tail length, both of which also reduce the risk of PSM rupture during transport. These results should help researchers understand how to better use surface decorations to achieve efficient pulmonary entry, which may provide useful guidance for the design of nano-based platforms for inhaled drug delivery.

Baryon Number Transfer Could Delay Quark–Hadron Transition in Cosmology

In the early Universe, strongly interacting matter was a quark–gluon plasma. Both lattice computations and heavy ion collision experiments, however, tell us that, in the absence of chemical potentials, no plasma survives at T < ∼ 150 MeV. The cosmological Quark–Hadron transition, however, seems to have been a crossover; cosmological consequences envisaged when it was believed to be a phase transition no longer hold. In this paper, we discuss whether even a crossover transition can leave an imprint that cosmological observations can seek or, vice versa, if there are questions cosmology should address to QCD specialists. In particular, we argue that it is still unclear how baryons (not hadrons) could form at the cosmological transition. A critical role should be played by diquark states, whose abundance in the early plasma needs to be accurately evaluated. We estimate that, if the number of quarks belonging to a diquark state, at the beginning of the cosmological transition, is < ∼ 1 : 10 6 , its dynamics could be modified by the process of B-transfer from plasma to hadrons. In turn, by assuming B-transfer to cause just mild perturbations and, in particular, no entropy input, we study the deviations from the tracking regime, in the frame of SCDEW models. We find that, in some cases, residual deviations could propagate down to primeval nuclesynthesis.

Challenge Integrity: The Cell-Penetrating Peptide BP100 Interferes with the Auxin-Actin Oscillator.

Actin filaments are essential for the integrity of the cell membrane. In addition to this structural role, actin can modulate signaling by altering polar auxin flow. On the other hand, the organization of actin filaments is modulated by auxin constituting a self-referring signaling hub. Although the function of this auxin–actin oscillator is not clear, there is evidence for a functional link with stress signaling activated by the NADPH oxidase Respiratory burst oxidase Homolog (RboH). In the current work, we used the cell-penetrating peptide BP100 to induce a mild and transient perturbation of membrane integrity. We followed the response of actin to the BP100 uptake in a green fluorescent protein (GFP)-tagged actin marker line of tobacco Bright Yellow 2 (BY-2) cells by spinning disc confocal microscopy. We observed that BP100 enters in a stepwise manner and reduces the extent of actin remodeling. This actin ‘freezing’ can be rescued by the natural auxin IAA, and mimicked by the auxin-efflux inhibitor 1-napthylphthalamic acid (NPA). We further tested the role of the membrane-localized NADPH oxidase RboH using the specific inhibitor diphenyl iodonium (DPI), and found that DPI acts antagonistically to BP100, although DPI alone can induce a similar actin ‘freezing’ as well. We propose a working model, where the mild violation of membrane integrity by BP100 stimulates RboH, and the resulting elevated levels of reactive oxygen species interfere with actin dynamicity. The mitigating effect of auxin is explained by competition of auxin- and RboH-triggered signaling for superoxide anions. This self-referring auxin–actin–RboH hub might be essential for integrity sensing.

Mechanical perturbations trigger endothelial nitric oxide synthase activity in human red blood cells.

Nitric oxide (NO), a vascular signaling molecule, is primarily produced by endothelial NO synthase. Recently, a functional endothelial NO synthase (eNOS) was described in red blood cells (RBC). The RBC-eNOS contributes to the intravascular NO pool and regulates physiological functions. However the regulatory mechanisms and clinical implications of RBC-eNOS are unknown. The present study investigated regulation and functions of RBC-eNOS under mechanical stimulation. This study shows that mechanical stimuli perturb RBC membrane, which triggers a signaling cascade to activate the eNOS. Extracellular NO level, estimated by the 4-Amino-5-Methylamino-2′, 7′-Difluorofluorescein Diacetate probe, was significantly increased under mechanical stimuli. Immunostaining and western blot studies confirmed that the mechanical stimuli phosphorylate the serine 1177 moiety of RBC-eNOS, and activates the enzyme. The NO produced by activation of RBC-eNOS in vortexed RBCs promoted important endothelial functions such as migration and vascular sprouting. We also show that mechanical perturbation facilitates nitrosylation of RBC proteins via eNOS activation. The results of the study confirm that mechanical perturbations sensitize RBC-eNOS to produce NO, which ultimately defines physiological boundaries of RBC structure and functions. Therefore, we propose that mild physical perturbations before, after, or during storage can improve viability of RBCs in blood banks.

Programing Effect Of Maternal High Fat/High Sucrose Diet On Cardiovascular Responses And Fos Expression following Air Jet And Restraint Stress

A high fat/high sucrose diet (HFS) and/or obesity during pregnancy are known stressors for programing hypertension in the adult offspring. Although the exact causative mechanisms are not fully elucidated, exaggerated cardiovascular (CV) and autonomic responses to psychological stress may be a contributing factor. However, the precise nature of the stressor and the central neural pathways via which the programed responses are mediated remain unknown. Our aim was to investigate the effect of a HFS maternal diet on blood pressure (BP) of adult male offspring at rest and in response to 2 psychological stressors of varying intensities. The central pathways involved in mediating these responses were also investigated by quantifying Fos expression in key CV control regions of the brain. The 2 stressors chosen were air jet stress (AJS), considered a moderate stressor, and restraint stress (RS), considered more severe in nature. Sprague Dawley dams were fed a HFS (21% fat, 34% (w/w) sucrose vs control, 4.8% fat, 0% sucrose) diet ad libitum for 4 weeks prior to mating until weaning. Adult offspring (9–12 months) were implanted with radiotelemetry BP transmitters and BP was recorded at rest for 24 hours, in response to the stress tests, and throughout a 2‐hour recovery period. CV parameters, including heart rate (HR) and mean BP (MnBP) were derived from the BP waveform. Following recovery, rats were perfused with 4% paraformaldehyde and brains processed immunohistochemically for Fos expression. Resting MnBP was similar between groups both at night (HFS, 101±2.3 mmHg; control, 97±2.5 mmHg) and day (HFS, 96±0.7 mmHg; control, 93±3.5 mmHg). There was also no difference in HR between groups. Interestingly, MnBP in HFS offspring was approximately 10 mmHg higher than controls in the resting period immediately preceding the stress tests. This suggests that even mild environmental perturbations, such as the presence of researchers in the laboratory, may have an impact on BP responses in HFS offspring. HFS offspring also exhibited greater increases in MnBP upon commencement of AJS (HFS, 25±5.4 mmHg; control, 13±3.1 mmHg) and delayed recovery. At 45 minutes post‐stress, MnBP was at 15% baseline in HFS, compared to 3.5% baseline in controls. RS caused similar increases in MnBP in both groups (HFS, 29±5.0 mmHg, control, 30±8.6 mmHg). Interestingly, initial analysis indicated that although RS produced greater CV responses than AJS in control offspring, this was not observed in HFS. Consistent with this, in control rats, RS evoked a 5‐fold increase in Fos labeling throughout the brainstem compared to baseline, while AJS caused a 3‐fold increase. Future analysis will determine the degree of Fos labeling in HFS offspring. The results suggest that maternal HFS programs a pro‐hypertensive phenotype characterised by exaggerated and extended BP responses to mild to moderate stress. RS evoked greater responses than AJS in control rats only, and this was consistent with greater Fos labelling in key CV nuclei in controls. Fos labelling in HFS is in progress.

Exponential Stability of Slowly Decaying Solutions to the Kinetic-Fokker-Planck Equation

The aim of the present paper is twofold: 1. We carry on with developing an abstract method for deriving decay estimates on the semigroup associated to non-symmetric operators in Banach spaces as introduced in [10]. We extend the method so as to consider the shrinkage of the functional space. Roughly speaking, we consider a class of operators written as a dissipative part plus a mild perturbation, and we prove that if the associated semigroup satisfies a decay estimate in some reference space then it satisfies the same decay estimate in another—smaller or larger—Banach space under the condition that a certain iterate of the “mild perturbation” part of the operator combined with the dissipative part of the semigroup maps the larger space to the smaller space in a bounded way. The cornerstone of our approach is a factorization argument, reminiscent of the Dyson series. 2. We apply this method to the kinetic Fokker-Planck equation when the spatial domain is either the torus with periodic boundary conditions, or the whole space with a confinement potential. We then obtain spectral gap estimates for the associated semigroup for various metrics, including Lebesgue norms, negative Sobolev norms, and the Monge-Kantorovich-Wasserstein distance W1.

Amelioration of Chronic Unpredictable Mild Stress-Induced Behavioural Perturbations by Noni Juice in Mice: Possible Involvement of Antioxidant System

Amelioration of Chronic Unpredictable Mild Stress-Induced Behavioural Perturbations by Noni Juice in Mice: Possible Involvement of Antioxidant System

Sensitive dependence of complex systems: an agent-based modelling demonstration

The objective of this paper is to provide insights about the phenomenon of sensitive dependence of complex systems on initial conditions i.e., the butterfly effect. An agent-directed simulation of a case study is presented to demonstrate and investigate this phenomenon. The case study used is exploring the impact of one person on a population's genome. A population growth simulation was created as a baseline. Every agent in the population was given a unique ten-digit identifier to represent their DNA coding. Other simulations were run with small perturbation factors introduced to the initial conditions. Results show that mild perturbations introduced to a population growth model can significantly alter the genetic structure of a population in the long term. Furthermore, the simulation revealed a positive relationship between the complexity of the system and the speed at which the butterfly effect emerges.

Sensitive dependence of complex systems: an agent-based modelling demonstration

The objective of this paper is to provide insights about the phenomenon of sensitive dependence of complex systems on initial conditions (i.e., the butterfly effect). An agent-directed simulation of a case study is presented to demonstrate and investigate this phenomenon. The case study used is exploring the impact of one person on a population's genome. A population growth simulation was created as a baseline. Every agent in the population was given a unique ten-digit identifier to represent their DNA coding. Other simulations were run with small perturbation factors introduced to the initial conditions. Results show that mild perturbations introduced to a population growth model can significantly alter the genetic structure of a population in the long term. Furthermore, the simulation revealed a positive relationship between the complexity of the system and the speed at which the butterfly effect emerges.

Exploration of Ammonia Production in Blue Green Algae By Bioelectrocatalytic Methods

Ammonia is an important compound to many industries around the world. Most of the fertilizers used by crop growers have ammonia as an essential ingredient. It can also be useful as a fuel source, offering greater energy density per unit than hydrogen, and greater safety. Currently, the predominant method for producing ammonia on an industrial scale is by the Haber-Bosch process. This process uses steam evolution of methane to provide H2 gas, which is then combined with N2 gas over an iron catalyst to form NH3. This process requires large amounts of energy as well as high temperatures and pressures. In this report, an alternative method for ammonia production is explored. With Anabaena Variabilis, a photosynthetic cyanobacteria, on a carbon electrode, ammonia can be generated at ambient temperatures and pressures at little energy cost, a few tenths of a volt.1,2 A bioelectrocatalytic device has been constructed by immobilizing whole cell a. variabilis in a Nafion film modified with a trimethyl octadecyl ammonium bromide (TMODA) salt at an electrode surface.3 The ammonium salt enlarges the pore size of the Nafion structure while neutralizing the acidic environment of the polymer, and provides a hospitable matrix for the algae cells. The polymer modified electrode provides the driving force and reductive microenvironment to facilitate production of NH3 by nitrogenase and nitrate/nitrite reductase enzymes present in a. variabilis. Ammonia production by cyanobacteria was increased from basal levels of 2.8 ± 0.4 µM produced over a two week period, to 22 ± 8 µM produced in 20 minutes under mild voltage perturbation, a roughly 104 increase in rate. Control of ammonia producing structures (nitrogenase or nitrate/nitrite reductase) can be accomplished by growing the algae with and without fixed sources of nitrogen in the growth media. The addition of nitrates and nitrites to the electrolyte during voltammetric perturbation varies linearly with ammonia increased with substrate.

Distributed forcing flow control in the wake of a blunt trailing edge profiled body using plasma actuators

A modern flow control technique for reducing the drag associated with the periodic shedding of von Kármán vortices in the wake of a blunt trailing edge profiled body is presented. The technique involves distributed forcing of the wake flow using an array of dielectric barrier discharge plasma actuators, with a spanwise spacing matched to the spanwise wavelength of the dominant secondary wake instability. The experiments include measurement of the velocity field in multiple vertical and horizontal planes in the wake using particle image velocimetry, as well as base pressure, at Reynolds numbers of 2000, 3000, and 5000 based on trailing edge thickness. The flow control technique causes elongation of the vortex formation region across the span, and significant reduction of the fluctuating and total drag forces, up to a maximum of 94% and 18%, respectively. The effectiveness of the flow control technique is shown to be dependent on the induced momentum coefficient. Proper orthogonal decomposition analysis is used to investigate the mechanism of interaction of the flow control technique with the wake flow. Two distinct flow regimes are observed depending on the induced momentum coefficient. The effect of the control on the wake flow structure in the first regime is similar to those observed in previous studies involving mild spanwise-periodic geometric perturbations at the trailing edge, where control leads to streamwise displacement of the vortices and a shift in shedding frequency. However, an incremental increase in the momentum coefficient leads to a second flow regime similar to those previously observed in the case of large-amplitude geometric perturbations, with an almost complete attenuation of vortex shedding in the near-wake region.

Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans.

Proteome stability is central to cellular function and the lifespan of an organism. This is apparent in muscle cells, where incorrect folding and assembly of the sarcomere contributes to disease and aging. Apart from the myosin-assembly factor UNC-45, the complete network of chaperones involved in assembly and maintenance of muscle tissue is currently unknown. To identify additional factors required for sarcomere quality control, we performed genetic screens based on suppressed or synthetic motility defects in Caenorhabditis elegans. In addition to ethyl methyl sulfonate-based mutagenesis, we employed RNAi-mediated knockdown of candidate chaperones in unc-45 temperature-sensitive mutants and screened for impaired movement at permissive conditions. This approach confirmed the cooperation between UNC-45 and Hsp90. Moreover, the screens identified three novel co-chaperones, CeHop (STI-1), CeAha1 (C01G10.8) and Cep23 (ZC395.10), required for muscle integrity. The specific identification of Hsp90 and Hsp90 co-chaperones highlights the physiological role of Hsp90 in myosin folding. Our work thus provides a clear example of how a combination of mild perturbations to the proteostasis network can uncover specific quality control modules.

Open questions: are the dynamics of ecological communities predictable?

Open questions: are the dynamics of ecological communities predictable?