Organs-on-chips: into the next decade

Organs-on-chips (OoCs) could be useful at various stages of drug discovery and development, providing insight regarding human organ physiology in both normal and disease contexts, as well as accurately predicting developmental drug safety and efficacy. This Review discusses the advances that have enabled OoCs to demonstrate physiological relevance, and the challenges and opportunities that need to be tackled to tap the full potential of OoC utility for translational research.Organs-on-chips (OoCs), also known as microphysiological systems or 'tissue chips' (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term. In the past decade, the OoC field has seen dramatic advances in the sophistication of biology and engineering, in the demonstration of physiological relevance and in the range of applications. These advances have also revealed new challenges and opportunities, and expertise from multiple biomedical and engineering fields will be needed to fully realize the promise of OoCs for fundamental and translational applications. This Review provides a snapshot of this fast-evolving technology, discusses current applications and caveats for their implementation, and offers suggestions for directions in the next decade

Inflating in a Better Racetrack

We present a new version of our racetrack inflation scenario which, unlike our original proposal, is based on an explicit compactification of type IIB string theory: the Calabi-Yau manifold P^4_[1,1,1,6,9]. The axion-dilaton and all complex structure moduli are stabilized by fluxes. The remaining 2 Kahler moduli are stabilized by a nonperturbative superpotential, which has been explicitly computed. For this model we identify situations for which a linear combination of the axionic parts of the two Kahler moduli acts as an inflaton. As in our previous scenario, inflation begins at a saddle point of the scalar potential and proceeds as an eternal topological inflation. For a certain range of inflationary parameters, we obtain the COBE-normalized spectrum of metric perturbations and an inflationary scale of M = 3 x 10^{14} GeV. We discuss possible changes of parameters of our model and argue that anthropic considerations favor those parameters that lead to a nearly flat spectrum of inflationary perturbations, which in our case is characterized by the spectral index n_s = 0.95.Comment: 20 pages, 7 figures. Brief discussion on the non-gaussianity of this model, one more figure of the field trajectories added as well as other minor changes to the tex

Oxidised cosmic acceleration

We give detailed proofs of several new no-go theorems for constructing flat four-dimensional accelerating universes from warped dimensional reduction. These new theorems improve upon previous ones by weakening the energy conditions, by including time-dependent compactifications, and by treating accelerated expansion that is not precisely de Sitter. We show that de Sitter expansion violates the higher-dimensional null energy condition (NEC) if the compactification manifold M is one-dimensional, if its intrinsic Ricci scalar R vanishes everywhere, or if R and the warp function satisfy a simple limit condition. If expansion is not de Sitter, we establish threshold equation-of-state parameters w below which accelerated expansion must be transient. Below the threshold w there are bounds on the number of e-foldings of expansion. If M is one-dimensional or R everywhere vanishing, exceeding the bound implies the NEC is violated. If R does not vanish everywhere on M, exceeding the bound implies the strong energy condition (SEC) is violated. Observationally, the w thresholds indicate that experiments with finite resolution in w can cleanly discriminate between different models which satisfy or violate the relevant energy conditions.Comment: v2: corrections, references adde

Big Corrections from a Little Higgs

We calculate the tree-level expressions for the electroweak precision observables in the SU(5)/SO(5) littlest Higgs model. The source for these corrections are the exchange of heavy gauge bosons, explicit corrections due to non-linear sigma-model dynamics and a triplet Higgs VEV. Weak isospin violating contributions are present because there is no custodial SU(2) global symmetry. The bulk of these weak isospin violating corrections arise from heavy gauge boson exchange while a smaller contribution comes from the triplet Higgs VEV. A global fit is performed to the experimental data and we find that throughout the parameter space the symmetry breaking scale is bounded by f > 4 TeV at 95% C.L. Stronger bounds on f are found for generic choices of the high energy gauge couplings. We find that even in the best case scenario one would need fine tuning of less than a percent to get a Higgs mass as light as 200 GeV.Comment: 20 pages, 5 figures included, typos fixed, comments on the effects of extra vector-like heavy fermions adde

Chiral effective field theories of the strong interactions

Effective field theories of the strong interactions based on the approximate chiral symmetry of QCD provide a model-independent approach to low-energy hadron physics. We give a brief introduction to mesonic and baryonic chiral perturbation theory and discuss a number of applications. We also consider the effective field theory including vector and axial-vector mesons.Comment: 22 pages, 9 figures, proceedings of "Many-Body Structure of Strongly Interacting Systems", Mainz, Germany, Feb. 23-25 201

On the Holographic RG-flow and the Low-energy, Strong Coupling, Large N Limit

From the AdS/CFT correspondence, we learn that the classical evolution of supergravity in the bulk can be reduced to a RG-flow equation for the dual low-energy, strongly coupled and large N gauge theory on the boundary. This result has been used to obtain interesting relations between the various terms in the gravitational part of the boundary effective action, in particular the term that affect the cosmological constant. It is found that once the cosmological constant is cancelled in the UV theory, the RG-flow symmetry of the boundary effective action automatically implies the existence of zero cosmological constant solutions that extend all the way into the IR. Given the standard (and well founded) contradiction between the RG-flow idea and the observational evidence of a small cosmological constant, this is considered to be an important progress, albeit incomplete, towards the final solution. Motivated by this success, it would be interesting to see whether this RG-stability extends outside the scope of strong 't Hooft coupling and large N regime that are implicitly assumed in the de Boer-Verlinde-Verlinde Hamilton-Jacobi formulation of the holographic RG-flow equations of the boundary theory. In this paper, we address this question. Taking into account the leading order corrections in the 1/N and $\alpha'/{R^2}$ parameters, we derive new bulk/boundary relations, from which one can read all the local terms in the boundary effective action. Next, we use the resulting constraints, to examine whether the RG-stability of the cosmological constant extends to the new coupling regime. It would be also interesting to use these constraints to study the Randall-Sundrum scenario in this case.Comment: 27 pages, LateX, no figures, minor changes, typos corrected and added more reference

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale

Search for a Higgs boson decaying into γ*γ→ℓℓγ with low dilepton mass in pp collisions at √s=8 TeV

A search is described for a Higgs boson decaying into two photons, one of which has an internal conversion to a muon or an electron pair ( ℓℓγ ). The analysis is performed using proton–proton collision data recorded with the CMS detector at the LHC at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 fb −1 . The events selected have an opposite-sign muon or electron pair and a high transverse momentum photon. No excess above background has been found in the three-body invariant mass range 12

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease