Hasil untuk "q-bio.SC"

Priyotosh Sil, Rahul Tiwari, Vasavi Garisetti et al.

Metabolic diseases such as type 2 diabetes and obesity represent a rapidly escalating global health burden, yet current therapeutic strategies largely target isolated symptoms or single molecular pathways. To this end, we developed an integrated computational pipeline leveraging knowledge graph, pathway analysis and network pharmacology to elucidate the multi-target mechanisms of Ayurvedic Single Herbal Drugs (SHDs). SHDs associated with diabetes and obesity were curated from the Ayurvedic Pharmacopoeia of India, followed by phytochemical identification using IMPPAT database, yielding a shortlist of 11 SHDs and their 188 phytochemicals after drug-likeness and bioavailability filtering. Subsequently, molecular targets of the phytochemicals in SHDs, disease-associated genes and therapeutic targets of FDA-approved drugs, were curated via integration of data from several databases. Pathway enrichment analysis revealed significant functional overlap between SHD-associated and disease-associated pathways. All curated data were embedded into a Neo4j-based knowledge graph, enabling SHD-disease intersection analysis that prioritized key disease-relevant targets, including PTPN1, GLP1R, and DPP4. Also, the SHD-Target-FDA-approved drug profile elucidated the molecular and mechanistic aspects of the SHDs as a phytochemical cocktail, and is in alignment with the clinically studied synergistic FDA-approved drug combinations. Network pharmacology based protein-protein interaction analysis identified PPARG as another central regulator. Using a quantitative framework, we identified phytochemical pairs within SHDs, which were structurally dissimilar and target-wise distinct, yet acted on shared or different disease-associated pathways, indicating complementary and potentially synergistic interactions. Molecular docking analysis of two selected druggable targets identified putative lead phytochemicals.

Yi Wang, Shu-Feng Zhou

Bantele and colleagues recently reported that repair of a single CRISPR/Cas9-induced DNA double-strand break (DSB) in the c-MYC topologically associated domain leads to a persistent depletion of chromatin interactions and long-term transcriptional attenuation across multiple generations of human cells. They interpret this observation as evidence for a previously unrecognized principle--"chromatin fatigue"--in which DSB repair generates a stable architectural defect that acts as a heritable impairment to genome function. Such an idea, if correct, would carry profound implications for genome biology, epigenetic inheritance, cancer evolution, aging, and the safety of therapeutic genome editing. However, our detailed reassessment of the experimental design, underlying assumptions, and data interpretation reveals that the evidence provided is inadequate to support these sweeping conclusions. Instead, the observed outcomes are more plausibly explained by a combination of Cas9 persistence, off-target DNA damage, repair-factor retention, MYC enhancer plasticity, and the well-documented genomic instability of HeLa cells. The study does not demonstrate mechanistic causality, does not exclude simpler explanations, and does not provide data consistent with true chromatin memory or heritable architectural change. Moreover, its statistical inferences are based on noisy measurements that fall within expected variability of unstable oncogenic loci. Here, we present a comprehensive critical analysis showing that the proposed model of chromatin fatigue is unsupported by the available evidence. We offer a corrected interpretation in which the chromatin landscape experiences a temporary, repair-associated perturbation that resolves without leaving enduring or heritable impairment.

Zitao Yang, Rebecca J. Rousseau, Sara D. Mahdavi et al.

Genes are connected in complex networks of interactions where often the product of one gene is a transcription factor that alters the expression of another. Many of these networks are based on a few fundamental motifs leading to switches and oscillators of various kinds. And yet, there is more to the story than which transcription factors control these various circuits. These transcription factors are often themselves under the control of effector molecules that bind them and alter their level of activity. Traditionally, much beautiful work has shown how to think about the stability of the different states achieved by these fundamental regulatory architectures by examining how parameters such as transcription rates, degradation rates and dissociation constants tune the circuit, giving rise to behavior such as bistability. However, such studies explore dynamics without asking how these quantities are altered in real time in living cells as opposed to at the fingertips of the synthetic biologist's pipette or on the computational biologist's computer screen. In this paper, we make a departure from the conventional dynamical systems view of these regulatory motifs by using statistical mechanical models to focus on endogenous signaling knobs such as effector concentrations rather than on the convenient but more experimentally remote knobs such as dissociation constants, transcription rates and degradation rates that are often considered. We also contrast the traditional use of Hill functions to describe transcription factor binding with more detailed thermodynamic models. This approach provides insights into how biological parameters are tuned to control the stability of regulatory motifs in living cells, sometimes revealing quite a different picture than is found by using Hill functions and tuning circuit parameters by hand.

Andre Archer, Brett J. Palmero, Charlotte Abrahamson et al.

Salmonella expresses bacterial microcompartments (MCPs) upon 1,2-propanediol exposure. MCPs are nanoscale protein-bound shells that encase enzymes for the cofactor-dependent 1,2-propanediol metabolism. They are hypothesized to limit exposure to the toxic intermediate, propionaldehyde, decrease cofactor involvement in competing reactions, and enhance flux. We construct a mass-action mathematical model of purified MCPs and calibrate parameters to measured metabolite concentrations. We constrain mass-action kinetic parameters to previously estimated Michaelis-Menten parameters. We identified two distinct fits with different dynamics in the pathway product, propionate, but similar goodness of fit. Across fits, we inferred that the MCP 1,2-propanediol and propionaldehyde permeability should be greater than 10^{-6} and 10^{-8} m/s, respectively. Our results identify parameter ranges consistent with prevailing theories that MCPs impose preferential diffusion to 1,2-propanediol over propionaldehyde, and sequester toxic propionaldehyde away from the cell cytosol. The bimodality of the posterior distribution arises from bimodality in the estimated coenzyme-A (CoA) permeability and inhibition rates. The MCP permeability to CoA was inferred to be either less than 10^{-8.8} m/s or greater than 10^{-7.3} m/s. In a high CoA permeability environment with low rates of CoA inhibition, enzymes produced metabolites by recycling (NAD+)/(NADH). In a low CoA permeability environment with high rates of CoA inhibition, enzymes required external NAD+/H to produce metabolites. Dynamics are consistent with prevailing hypotheses about MCP function to sequester toxic propionaldehyde, and additional collection of data points between 6 and 24 hours or characterization of enzyme inhibition rates could further reduce uncertainty and provide better permeability estimates.

Jochen Kursawe, Antoine Moneyron, Tobias Galla

Mathematical models of gene regulatory networks are widely used to study cell fate changes and transcriptional regulation. When designing such models, it is important to accurately account for sources of stochasticity. However, doing so can be computationally expensive and analytically untractable, posing limits on the extent of our explorations and on parameter inference. Here, we explore this challenge using the example of a simple auto-negative feedback motif, in which we incorporate stochastic variation due to transcriptional bursting and noise from finite copy numbers. We find that transcriptional bursting may change the qualitative dynamics of the system by inducing oscillations when they would not otherwise be present, or by magnifying existing oscillations. We describe multiple levels of approximation for the model in the form of differential equations, piecewise deterministic processes, and stochastic differential equations. Importantly, we derive how the classical chemical Langevin equation can be extended to include a noise term representing transcriptional bursting. This approximation drastically decreases computation times and allows us to analytically calculate properties of the dynamics, such as their power spectrum. We explore when these approximations break down and provide recommendations for their use. Our analysis illustrates the importance of accounting for transcriptional bursting when simulating gene regulatory network dynamics and provides recommendations to do so with computationally efficient methods.

Roberto Morán-Tovar, Michael Lässig

The immune response to an acute primary infection is a coupled process of antigen proliferation, molecular recognition by naive B cells, and their subsequent proliferation and antibody shedding. This process contains a fundamental problem: the recognition of an exponentially time-dependent antigen signal. Here we show that B cells can efficiently recognise new antigens by a tuned kinetic proofreading mechanism, where the molecular recognition machinery is adapted to the complexity of the immune repertoire. This process produces potent, specific and fast recognition of antigens, maintaining a spectrum of genetically distinct B cell lineages as input for affinity maturation. We show that the proliferation-recognition dynamics of a primary infection is a generalised Luria-Delbrück process, akin to the dynamics of the classic fluctuation experiment. This map establishes a link between signal recognition dynamics and evolution. We derive the resulting statistics of the activated immune repertoire: antigen binding affinity, expected size, and frequency of active B cell clones are related by power laws, which define the class of generalised Luria-Delbrück processes. Their exponents depend on the antigen and B cell proliferation rate, the number of proofreading steps, and the lineage density of the naive repertoire. We extend the model to include spatio-temporal processes, including the diffusion-recognition dynamics of a vaccination. Empirical data of activated mouse immune repertoires are found to be consistent with activation involving about three proofreading steps. The model predicts key clinical characteristics of acute infections and vaccinations, including the emergence of elite neutralisers and the effects of immune ageing. More broadly, our results establish infections and vaccinations as a new probe into the global architecture and functional principles of immune repertoires.

Goutham Kodakandla, Askar Akimzhanov, Darren Boehning

Plasma membrane calcium influx through ion channels is crucial for many events in cellular physiology. Cell surface stimuli lead to the production of inositol 1,4,5-trisphosphate (IP3), which binds to IP3 receptors in the endoplasmic reticulum (ER) to release calcium pools from the ER lumen. This leads to depletion of ER calcium pools which has been termed store-depletion. Store-depletion leads the dissociation of calcium ions from the EF-hand motif of the ER calcium sensor Stromal Interaction Molecule 1 (STIM1). This leads to a conformational change in STIM1 which helps it to interact with a plasma membrane (PM) at ER:PM junctions. At these ER:PM junctions, STIM1 binds to and activates a calcium channel known as Orai1 to form calcium-release activated calcium (CRAC) channels. Activation of Orai1 leads to calcium influx, known as store-operated calcium entry (SOCE). In addition to Orai1 and STIM1, the homologs of Orai1 and STIM1, such as Orai2/3 and STIM2 also play a crucial role in calcium homeostasis. The influx of calcium through the Orai channel activates a calcium current that has been termed CRAC currents. CRAC channels form multimers and cluster together in large macromolecular assemblies termed puncta. How these CRAC channels form puncta has been contentious since their discovery. In this review, we will outline the history of SOCE, the molecular players involved in this process (Orai and STIM proteins, TRP channels, SOCE-associated regulatory factor etc.), as well as the models that have been proposed to explain this important mechanism in cellular physiology.

Niranjan Sarpangala, Brooke Randell, Ajay Gopinathan et al.

A common type of cytoskeletal morphology involves multiple converging microbutubules with their minus ends collected and stabilized by a microtubule organizing center (MTOC) in the interior of the cell. This arrangement enables the ballistic transport of cargo bound to microtubules, both dynein mediated transport towards the MTOC and kinesin mediated transport away from it, interspersed with diffusion for unbound cargo-motor complexes. Spatial and temporal positioning of the MTOC allows for bidirectional transport towards and away from specific organelles and locations within the cell and also the sequestering and subsequent dispersal of dynein transported cargo. The general principles governing dynamics, efficiency and tunability of such transport in the MTOC vicinity is not fully understood. To address this, we develop a one-dimensional model that includes advective transport towards an attractor (such as the MTOC), and diffusive transport that allows particles to reach absorbing boundaries (such as cellular membranes). We calculated the mean first passage time (MFPT) for cargo to reach the boundaries as a measure of the effectiveness of sequestering (large MFPT) and diffusive dispersal (low MFPT). The MFPT experiences a dramatic growth in magnitude, transitioning from a low to high MFPT regime (dispersal to sequestering) over a window of cargo attachment/detachment rates that is close to in vivo values. We find that increasing either the attachment or detachment rate, while fixing the other, can result in optimal dispersal when the attractor is placed asymmetrically. Finally, we describe a rare event regime, where the escape location is exponentially sensitive to the attractor positioning. Our results suggest that structures such as the MTOC allow for the sensitive control of the spatial and temporal features of transport and corresponding function under physiological conditions.

B. Trumpower

The cytochrome bcl complex is an oligomeric membrane protein complex which is a component of the mitochondrial respiratory chain and of the electron transfer chains of numerous bacteria which use oxygen, nitrogen, and sulfur compounds as terminal electron acceptors. The cytochrome bcl complex also participates in the cyclic transfer of electrons to and from the photosynthetic reaction centers in anoxygenic photosynthetic bacteria. In all of these species the cytochrome bcl complex transfers electrons from ubiquinol to cytochrome c and links this electron transfer to translocation of protons across the membrane in which the bcl complex resides. The mechanism by which the cytochrome bcl complex links electron transfer to proton translocation is the protonmotive Q cycle (1). This protonmotive electron transfer is one of the most important mechanisms of cellular energy transduction, found in a phylogenetically diverse range of organisms (2). The purpose of this review is to explain the protonmotive Q cycle.

Misq Archivist, P. Rahmati, Ali Tafti et al.

During the last four decades, digital technologies have disrupted many industries. Car control systems have gone from mechanical to digital. Telephones have changed from sound boxes to portable computers. But have the firms that digitized their products and services become more valuable than firms that didn’t? Here we introduce the construct of digital proximity, which considers the interdependent activities of firms linked in an economic network. We then explore how the digitization of products and services affects a company’s Tobin’s q—the ratio of market value over assets—a measure of the intangible value of a firm. Our panel regression methods and robustness tests suggest the positive influence of a firm’s digital proximity on its Tobin’s q. This implies that firms able to come closer to the digital sector have increased their intangible value compared to those that have failed to do so. These findings contribute a new way of measuring digitization and its impact on firm performance that is complementary to traditional measures of information technology (IT) intensity.

D. Vernooy, Vladimir S. Ilchenko, H. Mabuchi et al.

Measurements of the quality factor Q approximately 8x10(9) are reported for the whispering-gallery modes (WGM's) of quartz microspheres for the wavelengths 670, 780, and 850 nm; these results correspond to finesse f approximately 2.2x10(6) . The observed independence of Q from wavelength indicates that losses for the WGM's are dominated by a mechanism other than bulk absorption in fused silica in the near infrared. Data obtained by atomic force microscopy combined with a simple model for surface scattering suggest that Q can be limited by residual surface inhomogeneities. Absorption by absorbed water can also explain why the material limit is not reached at longer wavelengths in the near infrared.

S. Spillane, T. Kippenberg, K. Vahala et al.

We investigate the suitability of toroidal microcavities for strong-coupling cavity quantum electrodynamics (QED). Numerical modeling of the optical modes demonstrate a significant reduction of the modal volume with respect to the whispering gallery modes of dielectric spheres, while retaining the high-quality factors representative of spherical cavities. The extra degree of freedom of toroid microcavities can be used to achieve improved cavity QED characteristics. Numerical results for atom-cavity coupling strength g, critical atom number No, and critical photon number no for cesium are calculated and shown to exceed values currently possible using Fabry-Perot cavities. Modeling predicts coupling rates g/2π exceeding 700 MHz and critical atom numbers approaching 10^(-7) in optimized structures. Furthermore, preliminary experimental measurements of toroidal cavities at a wavelength of 852 nm indicate that quality factors in excess of 108 can be obtained in a 50-µm principal diameter cavity, which would result in strong-coupling values of (g/(2π),n(0),N-0) = (86 MHz, 4.6 x 10^(-4), 1.0 x 10^(-3)).

Ilaria Incaviglia, Andreas Frutiger, Yves Blickenstorfer et al.

In recent years, cell-based assays have been frequently used in molecular interaction analysis. Cell-based assays complement traditional biochemical and biophysical methods, as they allow for molecular interaction analysis, mode of action studies and even drug screening processes to be performed under physiologically relevant conditions. In most cellular assays, biomolecules are usually labeled to achieve specificity. In order to overcome some of the drawbacks associated with label-based assays, we have recently introduced cell-based molography as a biosensor for the analysis of specific molecular interactions involving native membrane receptors in living cells. Here, we expand this assay to cytosolic protein-protein interactions. First, we created a biomimetic membrane receptor by tethering one cytosolic interaction partner to the plasma membrane. The artificial construct is then coherently arranged into a two-dimensional pattern within the cytosol of living cells. Thanks to the molographic sensor, the specific interactions between the coherently arranged protein and its endogenous interaction partners become visible in real-time without the use of a fluorescent label. This method turns out to be an important extension of cell-based molography because it expands the range of interactions that can be analyzed by molography to those in the cytosol of living cells.

M. Notomi, A. Shinya, S. Mitsugi et al.

We have demonstrated all-optical bistable switching operation of resonant-tunnelling devices with ultra-small high-Q Si photonic-crystal nanocavities. Due to their high Q/V ratio, the switching energy is extremely small in comparison with that of conventional devices using the same optical nonlinear mechanism. We also show that they exhibit all-opticaltransistor action by using two resonant modes. These ultrasmall unique nonlinear bistable devices have potentials to function as various signal processing functions in photonic-crystal-based optical-circuits.

S. Slussarenko, A. Murauski, T. Du et al.

Using a photoalignment technique with a sulphonic azo-dye as the surfactant aligning material, we fabricated electrically tunable liquid crystal q-plates with topological charge 0.5, 1.5 and 3 for generating optical vortex beams with definite orbital angular momentum (OAM) 1,3 and 6 per photon (in units of ¯h), respectively. We carried out several tests on our q-plates, including OAM tomography, finding excellent performances. These devices can have useful applications in general and quantum optics.

M. Gorodetsky, A. D. Pryamikov, V. Ilchenko

A. Golbraikh, A. Tropsha

H. Srivastava

T. Koornwinder, Rene F. Swarttouw

For H. Exton's q-analogue of the Bessel function (going back to W. Hahn in a special case, but different from F. H. Jackson's q-Bessel functions) we derive Hansen-Lommel type orthogonality relations, which, by a symmetry, turn out to be equivalent to orthogonality relations which are q-analogues of the Hankel integral transform pair. These results are implicit, in the context of quantum groups, in a paper by Vaksman and Korogodskii. As a specialization we get q-cosines and q-sines which admit q-analogues of the Fourier-cosine and Fourier-sine transforms

A. Visser

In this paper we study the theory Q. We prove a basic result that says that, in a sense explained in the paper, Q can be split into two parts. We prove some consequences of this result. (i) Q is not a poly-pair theory. This means that, in a strong sense, pairing cannot be defined in Q. (ii) Q does not have the Pudlák Property. This means that there two interpretations of $$\mathsf{S}^1_2$$S21 in Q which do not have a definably isomorphic cut. (iii) Q is not sententially equivalent with $$\mathsf{PA}^-$$PA-. This tells us that we cannot do much better than mutual faithful interpretability as a measure of sameness of Q and $$\mathsf{PA}^-$$PA-. We briefly consider the idea of characterizing Q as the minimal-in-some-sense theory of some kind modulo some equivalence relation. We show that at least one possible road towards this aim is closed.