T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo

The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell development and promotes leukemia and lymphoma. CDK4/6 kinase inhibitors are FDA approved for treatment of breast cancer patients and have been reported to enhance T cell-mediated anti-tumor immunity. The involvement of CDK6 in T cell functions remains enigmatic. We here investigated the role of CDK6 in CD8+ T cells, using previously generated CDK6 knockout (Cdk6-/-) and kinase-dead mutant CDK6 (Cdk6K43M) knock-in mice. RNA-seq analysis indicated a role of CDK6 in T cell metabolism and interferon (IFN) signaling. To investigate whether these CDK6 functions are T cell-intrinsic, we generated a T cell-specific CDK6 knockout mouse model (Cdk6fl/fl CD4-Cre). T cell-intrinsic loss of CDK6 enhanced mitochondrial respiration in CD8+ T cells, but did not impact on cytotoxicity and production of the effector cytokines IFN-γ and TNF-α by CD8+ T cells in vitro. Loss of CDK6 in peripheral T cells did not affect tumor surveillance of MC38 tumors in vivo. Similarly, while we observed an impaired induction of early responses to type I IFN in CDK6-deficient CD8+ T cells, we failed to observe any differences in the response to LCMV infection upon T cell-intrinsic loss of CDK6 in vivo. This apparent contradiction might at least partially be explained by the reduced expression of Socs1, a negative regulator of IFN signaling, in CDK6-deficient CD8+ T cells. Therefore, our data are in line with a dual role of CDK6 in IFN signaling; while CDK6 promotes early IFN responses, it is also involved in the induction of a negative feedback loop. These data assign CDK6 a role in the fine-tuning of cytokine responses.

Non-Hermitian route to higher-order topology in an acoustic crystal

Topological phases of matter are classified based on their Hermitian Hamiltonians, whose real-valued dispersions together with orthogonal eigenstates form nontrivial topology. In the recently discovered higher-order topological insulators (TIs), the bulk topology can even exhibit hierarchical features, leading to topological corner states, as demonstrated in many photonic and acoustic artificial materials. Naturally, the intrinsic loss in these artificial materials has been omitted in the topology definition, due to its non-Hermitian nature; in practice, the presence of loss is generally considered harmful to the topological corner states. Here, we report the experimental realization of a higher-order TI in an acoustic crystal, whose nontrivial topology is induced by deliberately introduced losses. With local acoustic measurements, we identify a topological bulk bandgap that is populated with gapped edge states and in-gap corner states, as the hallmark signatures of hierarchical higher-order topology. Our work establishes the non-Hermitian route to higher-order topology, and paves the way to exploring various exotic non-Hermiticity-induced topological phases.

Real-time observation of frequency Bloch oscillations with fibre loop modulation

Bloch oscillations (BOs) were initially predicted for electrons in a solid lattice to which a static electric field is applied. The observation of BOs in solids remains challenging due to the collision scattering and barrier tunnelling of electrons. Nevertheless, analogies of electron BOs for photons, acoustic phonons and cold atoms have been experimentally demonstrated in various lattice systems. Recently, BOs in the frequency dimension have been proposed and studied by using an optical micro-resonator, which provides a unique approach to controlling the light frequency. However, the finite resonator lifetime and intrinsic loss hinder the effect from being observed practically. Here, we experimentally demonstrate BOs in a synthetic frequency lattice by employing a fibre-loop circuit with detuned phase modulation. We show that a detuning between the modulation period and the fibre-loop roundtrip time acts as an effective vector potential and hence a constant effective force that can yield BOs in the modulation-induced frequency lattices. With a dispersive Fourier transformation, the pulse spectrum can be mapped into the time dimension, and its transient evolution can be precisely measured. This study offers a promising approach to realising BOs in synthetic dimensions and may find applications in frequency manipulations in optical fibre communication systems.

Human muscle stem cells are refractory to aging

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle micro-environment such as to disfavor the myogenic function of these cells.

Modeling high-resolution down-hole pressure transducer to achieve semi-distributed measurement in oil an d gas production wells

A full 3D computer model is developed to evaluate the performance impact of intrinsic loss and various geometrical features in high-resolution pressure transducer. The intrinsic loss is modeled as viscosity factors, which allows for a more efficient computer model. In this paper, the developed model is applied to yield an insight in the evolution of high-resolution down-hole pressure transducer, from Hewlett-Packard\texttrademark\, to Quartzdyne\texttrademark. As the quality factor is related to the inverse of the resolution, the transducing element optimization process to achieve the highest quality factor possible is investigated, considering the impact of crystal quality and geometrical features, such as: thickness, diameter and convexity (plano-convex and bi-convex). Temperature-dependent elastic constants are used to improve the model accuracy in modeling temperature effects on the vibrating resonator-type transducer. Boundary load conditions are used to simulate hydrostatic pressure. The simulations to extract the frequency shift are carried out in the range of $14\,psi$ ($96.5\,kPa$) to $20000\,psi$ ($137.89\,MPa$) and $0\,^oC$ to $200\,^oC$ for pressure and temperature, respectively, as such ranges are typically found in oil and gas wells. A discrepancy in the published temperature dependence has been found. A miniaturization path to achieve semi-distributed measurement in oil and gas production wells is presented.