The expanding horizons of network neuroscience: From description to prediction and control.

The field of network neuroscience has emerged as a natural framework for the study of the brain and has been increasingly applied across divergent problems in neuroscience. From a disciplinary perspective, network neuroscience originally emerged as a formal integration of graph theory (from mathematics) and neuroscience (from biology). This early integration afforded marked utility in describing the interconnected nature of neural units, both structurally and functionally, and underscored the relevance of that interconnection for cognition and behavior. But since its inception, the field has not remained static in its methodological composition. Instead, it has grown to use increasingly advanced graph-theoretic tools and to bring in several other disciplinary perspectives-including machine learning and systems engineering-that have proven complementary. In doing so, the problem space amenable to the discipline has expanded markedly. In this review, we discuss three distinct flavors of investigation in state-of-the-art network neuroscience: (i) descriptive network neuroscience, (ii) predictive network neuroscience, and (iii) a perturbative network neuroscience that draws on recent advances in network control theory. In considering each area, we provide a brief summary of the approaches, discuss the nature of the insights obtained, and highlight future directions.

A nonequilibrium force can stabilize 2D active nematics.

Suspensions of actively driven anisotropic objects exhibit distinctively nonequilibrium behaviors, and current theories predict that they are incapable of sustaining orientational order at high activity. By contrast, here we show that nematic suspensions on a substrate can display order at arbitrarily high activity due to a previously unreported, potentially stabilizing active force. This force moreover emerges inevitably in theories of active orientable fluids under geometric confinement. The resulting nonequilibrium ordered phase displays robust giant number fluctuations that cannot be suppressed even by an incompressible solvent. Our results apply to virtually all experimental assays used to investigate the active nematic ordering of self-propelled colloids, bacterial suspensions, and the cytoskeleton and have testable implications in interpreting their nonequilibrium behaviors.

Swimmer Suspensions on Substrates: Anomalous Stability and Long-Range Order.

We present a comprehensive theory of the dynamics and fluctuations of a two-dimensional suspension of polar active particles in an incompressible fluid confined to a substrate. We show that, depending on the sign of a single parameter, a state with polar orientational order is anomalously stable (or anomalously unstable), with a nonzero relaxation (or growth) rate for angular fluctuations, not parallel to the ordering direction, at zero wave number. This screening of the broken-symmetry mode in the stable state does lead to conventional rather than giant number fluctuations as argued by Bricard et al., Nature 503, 95 (2013), but their bend instability in a splay-stable flock does not exist and the polar phase has long-range order in two dimensions. Our theory also describes confined three-dimensional thin-film suspensions of active polar particles as well as dense compressible active polar rods, and predicts a flocking transition without a banding instability.

Correction: Negative stiffness and modulated states in active nematics.

Correction for 'Negative stiffness and modulated states in active nematics' by Pragya Srivastava et al., Soft Matter, 2016, 12, 8214-8225.

Negative stiffness and modulated states in active nematics.

We examine the dynamics of an active nematic liquid crystal on a frictional substrate. When frictional damping dominates over viscous dissipation, we eliminate flow in favor of active stresses to obtain a minimal dynamical model for the nematic order parameter, with elastic constants renormalized by activity. The renormalized elastic constants can become negative at large activity, leading to the selection of spatially inhomogeneous patterns via a mechanism analogous to that responsible for modulated phases arising at an equilibrium Lifshitz point. Tuning activity and the degree of nematic order in the passive system, we obtain a linear stability phase diagram that exhibits a nonequilibrium tricritical point where ordered, modulated and disordered phases meet. Numerical solution of the nonlinear equations yields a succession of spatial structures of increasing complexity with increasing activity, including kink walls and active turbulence, as observed in experiments on microtubule bundles confined at an oil-water interface. Our work provides a minimal model for an overdamped active nematic that reproduces all the nonequilibrium structures seen in simulations of the full active nematic hydrodynamics and provides a framework for understanding some of the mechanisms for selection of the nonequilibrium patterns in the language of equilibrium critical phenomena.

Cylindrical cellular geometry ensures fidelity of division site placement in fission yeast.

Successful cytokinesis requires proper assembly of the contractile actomyosin ring, its stable positioning on the cell surface and proper constriction. Over the years, many of the key molecular components and regulators of the assembly and positioning of the actomyosin ring have been elucidated. Here we show that cell geometry and mechanics play a crucial role in the stable positioning and uniform constriction of the contractile ring. Contractile rings that assemble in locally spherical regions of cells are unstable and slip towards the poles. By contrast, actomyosin rings that assemble on locally cylindrical portions of the cell under the same conditions do not slip, but uniformly constrict the cell surface. The stability of the rings and the dynamics of ring slippage can be described by a simple mechanical model. Using fluorescence imaging, we verify some of the quantitative predictions of the model. Our study reveals an intimate interplay between geometry and actomyosin dynamics, which are likely to apply in a variety of cellular contexts.

Activating membranes.

We present a general dynamical theory of a membrane coupled to an actin cortex containing polymerizing filaments with active stresses and currents, and demonstrate that active membrane dynamics [S. Ramaswamy et al., Phys. Rev. Lett. 84, 3494 (2000)] and spontaneous shape oscillations emerge from this description. We also consider membrane instabilities and patterns induced by the presence of filaments with polar orientational correlations in the tangent plane of the membrane. The dynamical features we predict should be seen in a variety of cellular contexts involving the dynamics of the membrane-cytoskeleton composite and cytoskeletal extracts coupled to synthetic vesicles.

Patterning of polar active filaments on a tense cylindrical membrane.

We study the dynamics and patterning of polar contractile filaments on the surface of a cylindrical cell using active hydrodynamic equations that incorporate couplings between curvature and filament orientation. Cables and rings spontaneously emerge as steady state configurations on the cylinder, and can be stationary or moving, helical or tilted segments moving along helical trajectories. We observe phase transitions in the steady state patterns upon changing cell diameter or motor-driven activity and make several testable predictions. Our results are relevant to the dynamics and patterning of a variety of active biopolymers in cylindrical cells.

Neem oil limonoids induces p53-independent apoptosis and autophagy.

Azadirachta indica, commonly known as neem, has a wide range of medicinal properties. Neem extracts and its purified products have been examined for induction of apoptosis in multiple cancer cell types; however, its underlying mechanisms remain undefined. We show that neem oil (i.e., neem), which contains majority of neem limonoids including azadirachtin, induced apoptotic and autophagic cell death. Gene silencing demonstrated that caspase cascade was initiated by the activation of caspase-9, whereas caspase-8 was also activated late during neem-induced apoptosis. Pretreatment of cancer cells with pan caspase inhibitor, z-VAD inhibited activities of both initiator caspases (e.g., caspase-8 and -9) and executioner caspase-3. Neem induced the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, suggesting the involvement of both caspase-dependent and AIF-mediated apoptosis. p21 deficiency caused an increase in caspase activities at lower doses of neem, whereas p53 deficiency did not modulate neem-induced caspase activation. Additionally, neem treatment resulted in the accumulation of LC3-II in cancer cells, suggesting the involvement of autophagy in neem-induced cancer cell death. Low doses of autophagy inhibitors (i.e., 3-methyladenine and LY294002) did not prevent accumulation of neem-induced LC3-II in cancer cells. Silencing of ATG5 or Beclin-1 further enhanced neem-induced cell death. Phosphoinositide 3-kinase (PI3K) or autophagy inhibitors increased neem-induced caspase-3 activation and inhibition of caspases enhanced neem-induced autophagy. Together, for the first time, we demonstrate that neem induces caspase-dependent and AIF-mediated apoptosis, and autophagy in cancer cells.

Package design as a branding tool in the cosmetic industry: consumers' perception vs. reality.

The product packaging plays a crucial role in attracting consumers, persuading them to buy the product, and serving as a vehicle for brand communication. Around 73% of purchasing decisions are made at the point of sale. An enhanced appeal and attractiveness of the product make the selection process easier for consumers. Design and marketing are two major areas that are inextricably linked to each other. Good design distinguishes brands and makes products stand out from the crowd, instilling a certain perception in consumers' minds. Brands that meet the criteria for creating a lasting impression may dominate the market on a global scale in reality. The consumer must perceive the quality that the brand has built into the package, which may be accomplished through various design elements. Colour, shape, images, material, and package convenience are all important design elements in cosmetic branding. These elements are combined well together in a design, but there is a lack of a holistic approach in the design elements that are in line with the consumers' perspective. These aspects are highlighted in the review paper, which also looks at the importance of product packaging in cosmetics branding, and tries to highlight a few ways in which brands can minimize the gap between desired brand message and consumer perception about the brand.

Information content of brain states is explained by structural constraints on state energetics.

Signal propagation along the structural connectome of the brain induces changes in the patterns of activity. These activity patterns define global brain states and contain information in accordance with their expected probability of occurrence. Being the physical substrate upon which information propagates, the structural connectome, in conjunction with the dynamics, determines the set of possible brain states and constrains the transition between accessible states. Yet, precisely how these structural constraints on state transitions relate to their information content remains unexplored. To address this gap in knowledge, we defined the information content as a function of the activation distribution, where statistically rare values of activation correspond to high information content. With this numerical definition in hand, we studied the spatiotemporal distribution of information content in functional magnetic resonance imaging (fMRI) data from the Human Connectome Project during different tasks, and report four key findings. First, information content strongly depends on cognitive context; its absolute level and spatial distribution depend on the cognitive task. Second, while information content shows similarities to other measures of brain activity, it is distinct from both Neurosynth maps and task contrast maps generated by a general linear model applied to the fMRI data. Third, the brain's structural wiring constrains the cost to control its state, where the cost to transition into high information content states is larger than that to transition into low information content states. Finally, all state transitions-especially those to high information content states-are less costly than expected from random network null models, thereby indicating the brains marked efficiency. Taken together, our findings establish an explanatory link between the information contained in a brain state and the energetic cost of attaining that state, thereby laying important groundwork for our understanding of large-scale cognitive computations.

Chlamydia pneumoniae heat shock protein 60 enhances expression of ERK, TLR-4 and IL-8 in atheromatous plaques of coronary artery disease patients.

Chlamydia pneumoniae heat shock protein (cHSP) 60 is produced during chronic chlamydial infection and activate innate immune and inflammatory responses thereby contributing to atherogenesis. However, to date there is no apparent signaling cascade delineated in human atherosclerotic plaques in C. pneumoniae positive coronary artery disease (CAD) patients. Atherosclerotic plaques were obtained from 40 CAD patients (28 men, 12 women) attending Department of Cardio Thoracic and Vascular Surgery Safdarjung Hospital, New Delhi. Atherosclerotic plaques were used for gene expression studies at RNA level by real-time PCR and to study expression of ERK1/2, JNK1/2, NF-kB, IkkB and MCP-1 at protein level by immunoblotting. Significantly higher (p < 0.001) RNA expression was found for IL-8, TLR-2/4, TGF-ß, ICAM1, VCAM1 and MAPKinase genes, whereas significantly lower (p < 0.001) RNA expression for SMAD4, IkkB, BRCA1 and IL-10 was detected in cHSP60-positive atheromatous plaque of CAD patients. Moreover, at proteins level pERK1/2 (p = 0.05), NF-kB (p = 0.017), MCP-1 (p = 0.011) was higher and IkkB expression was lower (p = 0.038) in cHSP60-positive atheromatous plaque of CAD patients. This study by using human atheromatous plaques at RNA and protein levels demonstrated higher expression of TLR-2/4, IL-8, ICAM1, VCAM1, ERK1/2 and NF-kB in cHSP60-positive CAD patients.

Phytochemical Screening and In-Vitro Antibacterial and Anticancer Activity of Crude Extract of Matricaria aurea.

BACKGROUND: Infectious diseases constantly represent the source of sickness as well as mortality in human beings. Herbal applications in human life through using plants for antibacterial and anticancer activity have shown the potential medicinal outcome. OBJECTIVES: To evaluate the antibacterial and anticancer activities of the crude extract of Matricaria aurea. MATERIALS AND METHODS: The antibacterial activity of the crude flowers of M. aurea extract was examined against reference and clinical bacterial strains by agar well diffusion method. Minimum inhibitory concentrations and minimum bactericidal concentrations were determined by micro broth dilution assays using MH broth. Herbal extract was employed over human breast adenocarcinoma cell line (MCF-7), hepatocellular carcinoma cell line (HepG-2) and colorectal adenocarcinoma cell line (HCT-116) to optimize cancer cells proliferation by SRB assay. RESULTS: The data has shown that the extract from M. aurea had significant antimicrobial activity against the tested microorganisms. The plant extract showed higher antibacterial activity against the reference strain of Streptococcus pyogenes. The MIC and MBC varied between 0.38-12.5 mg/ml and 3.1-200 mg/ml respectively. Synergy study elucidated the significant bacteriostatic effect of M. aurea extract on S. aureus and S. saprophyticus. The data of SRB assay deliver the potential anticancer activity through cell death. CONCLUSION: This study delivers innovative information that M. aurea possessed excellent bio-activities against pathogenic microbes and cancer cells, which drive attention for further research to explore the active components responsible for biological efficacies.

Higher expression of ferritin protects Chlamydia trachomatis infected HeLa 229 cells from reactive oxygen species mediated cell death.

Apoptosis plays an important role in modulating the pathogenesis of a variety of infectious diseases. Chlamydial infection protects cells against different forms of apoptosis: extrinsic, intrinsic, and granzyme B mediated. Redox reactions are central to the life and death decision of cells and pathogens and an intimate relationship exists between oxidative stress and iron metabolism. The link between redox status and ferritin was largely unexplored in chlamydia-infected cells. In the present study, we showed that Chlamydia trachomatis (CT) infection induced FHC protein in HeLa cells. FHC induction by CT-infected cells stably expressing FHC blunted ROS production compared with mock infected cells, and the infected cells were relatively resistant to apoptosis induced by H2O2. We also demonstrated that endogenous FHC overexpression correlates well with the stabilization of the mitochondrial membrane potential in CT-infected cells. Increased expression of FHC is independent of iron supplementation (FAC) and depletion (DFO) in CT-infected cells. These data suggest that FHC up-regulation is an acute response of HeLa cells against CT infection and that FHC exerts anti-apoptotic activity against oxidative stress.

Decreased susceptibility to azithromycin and doxycycline in clinical isolates of Chlamydia trachomatis obtained from recurrently infected female patients in India.

BACKGROUND: Recurrent genital Chlamydia trachomatis infection often results in serious sequelae and has a major impact on reproductive health. MATERIALS AND METHODS: Recurrent infections were determined in symptomatic female patients. In vitro susceptibility assay was performed for azithromycin and doxycycline using the cell culture technique against 21 clinical isolates obtained from C. trachomatis-positive patients including those who were recurrently infected. RESULTS: Thirteen isolates (61.9%) were found to be susceptible to azithromycin and doxycycline with minimum inhibitory concentration (MIC) values ≤0.125 and ≤0.25 µg/ml, respectively. Eight isolates (38%) were found to be less susceptible to the drugs. Two of them had MICs of 8 µg/ml for both the drugs and could not be completely eradicated as observed by minimum bactericidal concentration assay. CONCLUSIONS: Decreased antibiotic susceptibility to the current first-line drugs (azithromycin and doxycycline) for chlamydial infection treatment was observed in isolates obtained from recurrently infected patients.

Models of communication and control for brain networks: distinctions, convergence, and future outlook.

Recent advances in computational models of signal propagation and routing in the human brain have underscored the critical role of white-matter structure. A complementary approach has utilized the framework of network control theory to better understand how white matter constrains the manner in which a region or set of regions can direct or control the activity of other regions. Despite the potential for both of these approaches to enhance our understanding of the role of network structure in brain function, little work has sought to understand the relations between them. Here, we seek to explicitly bridge computational models of communication and principles of network control in a conceptual review of the current literature. By drawing comparisons between communication and control models in terms of the level of abstraction, the dynamical complexity, the dependence on network attributes, and the interplay of multiple spatiotemporal scales, we highlight the convergence of and distinctions between the two frameworks. Based on the understanding of the intertwined nature of communication and control in human brain networks, this work provides an integrative perspective for the field and outlines exciting directions for future work.

Mechanochemical Crosstalk Produces Cell-Intrinsic Patterning of the Cortex to Orient the Mitotic Spindle.

Proliferating animal cells are able to orient their mitotic spindles along their interphase cell axis, setting up the axis of cell division, despite rounding up as they enter mitosis. This has previously been attributed to molecular memory and, more specifically, to the maintenance of adhesions and retraction fibers in mitosis [1-6], which are thought to act as local cues that pattern cortical Gαi, LGN, and nuclear mitotic apparatus protein (NuMA) [3, 7-18]. This cortical machinery then recruits and activates Dynein motors, which pull on astral microtubules to position the mitotic spindle. Here, we reveal a dynamic two-way crosstalk between the spindle and cortical motor complexes that depends on a Ran-guanosine triphosphate (GTP) signal [12], which is sufficient to drive continuous monopolar spindle motion independently of adhesive cues in flattened human cells in culture. Building on previous work [1, 12, 19-23], we implemented a physical model of the system that recapitulates the observed spindle-cortex interactions. Strikingly, when this model was used to study spindle dynamics in cells entering mitosis, the chromatin-based signal was found to preferentially clear force generators from the short cell axis, so that cortical motors pulling on astral microtubules align bipolar spindles with the interphase long cell axis, without requiring a fixed cue or a physical memory of interphase shape. Thus, our analysis shows that the ability of chromatin to pattern the cortex during the process of mitotic rounding is sufficient to translate interphase shape into a cortical pattern that can be read by the spindle, which then guides the axis of cell division.

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells.

The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.