Modern approaches to understanding stress and disease susceptibility: A review with special emphasis on respiratory disease

Studies in animals and humans link both physical and psychological stress with an increased incidence and severity of respiratory infections. For this manuscript we define stress as the physiological responses an individual undergoes while adjusting to a continually changing environment. It is known that stressors of various types (psychological/physical) can alter the physiological levels of certain hormones, chemokines and cytokines. These alterations send information to the central nervous system to take necessary action which then sends messages to appropriate organs/tissues/cells to respond. These messages can either activate or suppress the immune system as needed and failure to compensate for this by the body can lead to serious health-related problems. Little is known how stress affects disease susceptibility, yet understanding this mechanism is important for developing effective treatments, and for improving health and food quality. The current review focuses on (a) the effects of psychological stressors in humans and animals, (b) various methodologies employed to understand stress responses and their outcomes, and (c) the current status of the attempts to correlate stress and disease with respiratory disease as model system. The methodologies included in this review span traditional epidemiological, behavioral and immunological studies to current high throughput genomic, proteomic, metabolomic/metabonomic approaches. With the advent of various newer omics and bioinformatics methodologies we postulate that it will become feasible to understand the mechanisms through which stress can influence disease onset. Although the literature in this area is limited because of the infancy of this research area, the objective of this review is to illustrate the power of new approaches to address complex biological questions. These new approaches will also aid in our understanding how these processes are related to the dynamics and kinetics of changes in expression of multiple genes at various levels

COA6 facilitates cytochrome c oxidase biogenesis as thiol-reductase for copper metallochaperones in mitochondria.

The mitochondrial cytochrome c oxidase, the terminal enzyme of the respiratory chain, contains heme and copper centers for electron transfer. The conserved COX2 subunit contains the CuA site, a binuclear copper center. The copper chaperones SCO1, SCO2, and COA6 are required for CuA center formation. Loss of function of these chaperones and the concomitant cytochrome c oxidase deficiency cause severe human disorders. Here we analyzed the molecular function of COA6 and the consequences of COA6 deficiency for mitochondria. Our analyses show that loss of COA6 causes combined complex I and complex IV deficiency and impacts membrane potential driven protein transport across the inner membrane. We demonstrate that COA6 acts as a thiol-reductase to reduce disulphide bridges of critical cysteine residues in SCO1 and SCO2. Cysteines within the CX3CXNH domain of SCO2 mediate its interaction with COA6 but are dispensable for SCO2-SCO1 interaction. Our analyses define COA6 as thiol-reductase, which is essential for CuA biogenesis

Statistical Isotropy violation of the CMB brightness fluctuations

Certain anomalies at large angular scales in the cosmic microwave background measured by WMAP have been suggested as possible evidence of breakdown of statistical isotropy(SI). Most CMB photons free-stream to the present from the surface of last scattering. It is thus reasonable to expect statistical isotropy violation in the CMB photon distribution observed now to have originated from SI violation in the baryon-photon fluid at last scattering, in addition to anisotropy of the primordial power spectrum studied earlier in literature. We consider the generalized anisotropic brightness distribution fluctuations, $\Delta(\vec{k}, \hat{n}, \tau)$ (at conformal time $\tau$) in contrast to the SI case where it is simply a function of $|\vec{k}|$ and $\hat{k} \cdot \hat{n}$. The brightness fluctuations expanded in Bipolar Spherical Harmonic (BipoSH) series, can then be written as $\Delta_{\ell_1 \ell_2}^{L M}(\vec{k}, \tau)$ where $L > 0$ terms encode deviations from statistical isotropy. We study the evolution of $\Delta_{\ell_1 \ell_2}^{L M}(\vec{k}, \tau)$ from non-zero terms $\Delta_{\ell_3 \ell_4}^{L M}(\vec{k}, \tau_s)$ at last scattering. Similar to the SI case, power at small spherical harmonic (SH) multipoles of $\Delta_{\ell_3 \ell_4}^{L M}(\vec{k},\tau_s)$ at the last scattering, is transferred to $\Delta_{\ell_1 \ell_2}^{L M}(\vec{k}, \tau)$ at larger SH multipoles. The structural similarity is more apparent in the asymptotic expression for large values of the final SH multipoles. This formalism allows an elegant identification of any SI violation observed today to a possible origin in the SI violation present in the baryon-photon fluid (eg., due to the presence of significant magnetic field).Comment: 14 pages, 4 figures, added illustrative example of SI violation in baryon-photon fluid, matches version accepted for publication in Phys. Rev.

Effect of Stress on Viral–Bacterial Synergy in Bovine Respiratory Disease: Novel Mechanisms to Regulate Inflammation

The severity of bovine respiratory infections has been linked to a variety offactors, including environmental and nutritional changes, transportation, and socialreorganization of weaned calves. Fatal respiratory infections, however, usually occurwhen a primary viral infection compromises host defences and enhances the severityof a secondary bacterial infection. This viral–bacterial synergy can occur by a numberof different mechanisms and disease challenge models have been developed to analysehost responses during these respiratory infections. A primary bovine herpesvirus-1(BHV-1) respiratory infection followed by a secondary challenge with Mannheimia haemolyticaresults in fatal bovine respiratory disease (BRD) and host responses to these two pathogens have been studied extensively. We used this disease model todemonstrate that stress significantly altered the viral–bacterial synergy resulting infatal BRD. Functional genomic analysis revealed that BHV-1 infection enhanced toll-likereceptors (TLR) expression and increased pro-inflammatory responses whichcontribute to the severity of a Mannheimia haemolytica infection. TLRs play a criticalrole in detecting bacterial infections and inducing pro-inflammatory responses. It isdifficult to understand, however, how stress-induced corticosteroids could enhancethis form of viral–bacterial synergy. Nuclear translocation of the glucocorticoidreceptor activates cell signalling pathways which inhibit both TLR signallingand pro-inflammatory responses. The apparent conundrum between stress-inducedcorticosteroids and enhanced BRD susceptibility is discussed in terms of present data and previous investigations of stress and respiratory disease

3D Magneto-buoyancy-thermocapillary convection of CNT-water nanofluid in the presence of a magnetic field

Anumerical study is performed to investigate the effects of adding Carbon Nano Tube (CNT) and applying a magnetic field in two directions (vertical and horizontal) on the 3D-thermo-capillary natural convection. The cavity is differentially heated with a free upper surface. Governing equations are solved using the finite volume method. Results are presented in term of flow structure, temperature field and rate of heat transfer. In fact, results revealed that the flow structure and heat transfer rate are considerably affected by the magnitude and the direction of the magnetic field, the presence of thermocapillary forces and by increasing nanoparticles volume fraction. In opposition, the increase of the magnetic field magnitude leads to the control the flow causing flow stabilization by merging vortexes and reducing heat transfer rate. © 2020 by the authors

Generalized Fisher matrices

16.04.15 KB Ok to add accepted version to spira

GW190814: Gravitational Waves from the Coalescence of a 23 Solar Mass Black Hole with a 2.6 Solar Mass Compact Object

We report the observation of a compact binary coalescence involving a 22.2 - 24.3 M⊙ black hole and a compact object with a mass of 2.50 - 2.67 M⊙ (all measurements quoted at the 90% credible level). The gravitational-wave signal, GW190814, was observed during LIGO\u27s and Virgo\u27s third observing run on August 14, 2019 at 21:10:39 UTC and has a signal-to-noise ratio of 25 in the three-detector network. The source was localized to 18.5 deg2 at a distance of 241+41−45 Mpc; no electromagnetic counterpart has been confirmed to date. The source has the most unequal mass ratio yet measured with gravitational waves, 0.112+0.008−0.009, and its secondary component is either the lightest black hole or the heaviest neutron star ever discovered in a double compact-object system. The dimensionless spin of the primary black hole is tightly constrained to ≤0.07. Tests of general relativity reveal no measurable deviations from the theory, and its prediction of higher-multipole emission is confirmed at high confidence. We estimate a merger rate density of 1-23 Gpc−3 yr−1 for the new class of binary coalescence sources that GW190814 represents. Astrophysical models predict that binaries with mass ratios similar to this event can form through several channels, but are unlikely to have formed in globular clusters. However, the combination of mass ratio, component masses, and the inferred merger rate for this event challenges all current models for the formation and mass distribution of compact-object binaries

Overexpression of branched-chain amino acid aminotransferases rescues the growth defects of cells lacking the Barth syndrome-related gene TAZ1.

The yeast protein Taz1 is the orthologue of human Tafazzin, a phospholipid acyltransferase involved in cardiolipin (CL) remodeling via a monolyso CL (MLCL) intermediate. Mutations in Tafazzin lead to Barth syndrome (BTHS), a metabolic and neuromuscular disorder that primarily affects the heart, muscles, and immune system. Similar to observations in fibroblasts and platelets from patients with BTHS or from animal models, abolishing yeast Taz1 results in decreased total CL amounts, increased levels of MLCL, and mitochondrial dysfunction. However, the biochemical mechanisms underlying the mitochondrial dysfunction in BTHS remain unclear. To better understand the pathomechanism of BTHS, we searched for multi-copy suppressors of the taz1Δ growth defect in yeast cells. We identified the branched-chain amino acid transaminases (BCATs) Bat1 and Bat2 as such suppressors. Similarly, overexpression of the mitochondrial isoform BCAT2 in mammalian cells lacking TAZ improves their growth. Elevated levels of Bat1 or Bat2 did not restore the reduced membrane potential, altered stability of respiratory complexes, or the defective accumulation of MLCL species in yeast taz1Δ cells. Importantly, supplying yeast or mammalian cells lacking TAZ1 with certain amino acids restored their growth behavior. Hence, our findings suggest that the metabolism of amino acids has an important and disease-relevant role in cells lacking Taz1 function. KEY MESSAGES: Bat1 and Bat2 are multi-copy suppressors of retarded growth of taz1Δ yeast cells. Overexpression of Bat1/2 in taz1Δ cells does not rescue known mitochondrial defects. Supplementation of amino acids enhances growth of cells lacking Taz1 or Tafazzin. Altered metabolism of amino acids might be involved in the pathomechanism of BTSH

High-efficacy subcellular micropatterning of proteins using fibrinogen anchors.

Protein micropatterning allows proteins to be precisely deposited onto a substrate of choice and is now routinely used in cell biology and in vitro reconstitution. However, drawbacks of current technology are that micropatterning efficiency can be variable between proteins and that proteins may lose activity on the micropatterns. Here, we describe a general method to enable micropatterning of virtually any protein at high specificity and homogeneity while maintaining its activity. Our method is based on an anchor that micropatterns well, fibrinogen, which we functionalized to bind to common purification tags. This enhances micropatterning on various substrates, facilitates multiplexed micropatterning, and dramatically improves the on-pattern activity of fragile proteins like molecular motors. Furthermore, it enhances the micropatterning of hard-to-micropattern cells. Last, this method enables subcellular micropatterning, whereby complex micropatterns simultaneously control cell shape and the distribution of transmembrane receptors within that cell. Altogether, these results open new avenues for cell biology

Influence of heavy modes on perturbations in multiple field inflation

We investigate linear cosmological perturbations in multiple field inflationary models where some of the directions are light while others are heavy (with respect to the Hubble parameter). By integrating out the massive degrees of freedom, we determine the multi-dimensional effective theory for the light degrees of freedom and give explicitly the propagation matrix that replaces the effective sound speed of the one-dimensional case. We then examine in detail the consequences of a sudden turn along the inflationary trajectory, in particular the possible breakdown of the low energy effective theory in case the heavy modes are excited. Resorting to a new basis in field space, instead of the usual adiabatic/entropic basis, we study the evolution of the perturbations during the turn. In particular, we compute the power spectrum and compare with the result obtained from the low energy effective theory.Comment: 24 pages, 13 figures; v2 substantial changes in sec.V; v3 matching the published version on JCA