A Unified Model for Non-Fickian Diffusion and Anomalous Swelling of Glassy Polymer Gels.

A sheet of glassy polymers placed in a solvent shows swelling behaviors quite different from that of soft polymers (rubbers and gels). (1) Non-Fickian diffusion (called case II diffusion): As solvent permeates into the sample, a sharp front is created between the swollen part and the glassy part, and it moves toward the center at constant speed. (2) Nonmonotonous swelling: The thickness of the sample first increases and then decreases toward the equilibrium value. Here we propose a theory to explain such anomalous behavior by extending the previous theory for swelling of soft gels. We regard the material as a continuum mixture of a glassy polymer network and solvent. We assume that the polymer network is a viscoelastic gel of glassy polymers, and its relaxation time depends strongly on solvent concentration. We show that this theory explains the above two characteristics of glassy polymers in a simple and unified framework. The theory predicts how the permeation speed of the solvent and the characteristic times of the swelling process depend on material parameters and experimental conditions, which can be checked experimentally.

Temperature-Dependent Upregulation of Per2 Protein Expression Is Mediated by eIF2α Kinases PERK and PKR through PI3K Activation.

Temperature-dependent translational control of the core clock gene Per2 plays an important role in establishing entrainment of the circadian clock to physiological body temperature cycles. Previously, we found an involvement of the phosphatidylinositol 3-kinase (PI3K) in causing Per2 protein expression in response to a warm temperature shift (WTS) within a physiological range (from 35 to 38.5 °C). However, signaling pathway mediating the Per2 protein expression in response to WTS is only sparsely understood. Additional factor(s) other than PI3K remains unknown. Here we report the identification of eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), as a novel mediator of WTS-dependent Per2 protein expression. Canonically, eIF2α has been regarded as a major downstream target of PERK and PKR. However, we found that PERK and PKR mediate WTS response of Per2 in a manner not involving eIF2α. We observed that PERK and PKR serve as an upstream regulator of PI3K rather than eIF2α in the context of WTS-dependent Per2 protein expression. There have been studies reporting PI3K activation occurring depending on PERK and PKR, while its physiological contribution has remained elusive. Our finding therefore not only helps to enrich the knowledge of how WTS affects Per2 protein expression but also extends the region of cellular biology involving the PERK/PKR-mediated PI3K activation to include entrainment-mechanism of the circadian clock.

An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.

The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.

Effect of fluid viscoelasticity, shear stress, and interface tension on the lift force in lubricated contacts.

We consider a cylinder immersed in viscous fluid moving near a flat substrate covered by an incompressible viscoelastic fluid layer, and study the effect of the fluid viscoelasticity on the lift force exerted on the cylinder. The lift force is zero when the viscoelastic layer is not deformed, but becomes non-zero when it is deformed. We calculate the lift force by considering both the tangential stress and the normal stress applied at the surface of the viscoelastic layer. Our analysis indicates that as the layer changes from the elastic limit to the viscous limit, the lift force decreases with the decrease of the Deborah number (De). For small De, the effect of the layer elasticity is taken over by the surface tension and the lift force can become negative. We also show that the tangential stress and the interface slip velocity (the surface velocity relative to the substrate), which have been ignored in the previous analysis, give important contributions to the lift force. Especially for thin elastic layers, they give dominant contributions to the lift force.

Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm.

Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology.

Universality in the Dynamics of Vesicle Translocation through a Hole.

We analyze the translocation process of a spherical vesicle, made of a membrane and incompressible fluid, through a hole smaller than the vesicle size, driven by pressure difference ΔP. We show that such a vesicle shows certain universal characteristics, which are independent of the details of the membrane elasticity: (i) there is a critical pressure ΔPc below which no translocation occurs; (ii) ΔPc decreases to zero as the vesicle radius R0 approaches the hole radius a, satisfying the scaling relation ΔPc ∼ (R0 - a)3/2; and (iii) the translocation time τ diverges as ΔP decreases to ΔPc, satisfying the scaling relation τ ∼ (ΔP - ΔPc)-1/2.

Interplay of Consolidation Fronts and Cracks in Drying Colloidal Coatings and Its Application in Controlling Crack Pattern Formation.

Cracks are frequently observed in drying colloidal coatings. Although a rich collection of crack patterns has been reported, the systematic study on how cracks grow into the final morphology during the drying process remains elusive. In this work, we use directional drying channels with wedge-shaped edges of different angles to study the interplay of advancing consolidation fronts and propagating cracks. We found that although the shape of the advancing consolidation fronts is altered by the drying edge, the growth direction of the following cracks remains perpendicular to the consolidation fronts during the whole drying process, resulting in cracks with a large curvature. We rationalize the evolution of consolidation fronts with the distribution of capillary pressure revealed by a Laplace model. Further, the growth direction of cracks can be explained by the fracture mechanics mechanism that the main orientation of internal tensile stresses developed during the consolidation determines the crack growth direction. Utilizing this understanding, wavy crack patterns are generated in rectangular drying channels with an alternating temperature field, demonstrating a feasible method of designing and controlling drying-induced crack patterns for micro-/nano-fabrication applications.

Diffusion Limited Escape Rate of a Complex Molecule in Multi-dimensional Confinement.

The rate at which a Brownian particle confined in a closed space escapes from the space by passing through a narrow passage is called the escape rate. The escape rate is relevant to many diffusion limited processes in polymer and colloidal systems, such as colloidal aggregation, polymerization reaction, polymer translocation through a membrane, etc. Here, we propose a variational principle to calculate the escape rate of complex molecules doing Brownian motion in a multi-dimensional phase space. We propose a regional minimization method in which we divide the whole phase space into regions, conduct the minimization for each region, and combine the results to get the minimum in the entire space. As an example, we discuss (1) the escape rate of a point particle that escapes from a confinement passing through a long corridor and (2) the escape rate of a rod-like particle that escapes through a small hole made in the wall of the confinement.

Nmu/Nms/Gpr176 Triple-Deficient Mice Show Enhanced Light-Resetting of Circadian Locomotor Activity.

The suprachiasmatic nucleus (SCN) is the master circadian clock in mammals and is properly entrained by environmental light cycle. However, the molecular mechanism(s) determining the magnitude of phase shift by light is still not fully understood. The orphan G-protein-coupled receptor Gpr176 is enriched in the SCN, controls the pace (period) of the circadian rhythm in behavior but is not apparently involved in the light entrainment; Gpr176-/- animals display a shortened circadian period in constant darkness but their phase-resetting responses to light are normal. Here, we performed microarray analysis and identified enhanced mRNA expression of neuromedin U (Nmu) and neuromedin S (Nms) in the SCN of Gpr176-/- mice. By generating C57BL/6J-backcrossed Nmu/Nms/Gpr176 triple knockout mice, we noted that the mutant mice had a greater magnitude of phase shift in response to early subjective night light than wildtype mice, while Nmu/Nms double knockout mice as well as Gpr176 knockout mice are normal in the phase shifts induced by light. At the molecular level, Nmu-/-Nms-/-Gpr176-/- mice had a reduced induction of Per1 and cFos mRNA expression in the SCN by light and mildly upregulated circadian expression of Per2, Prok2, Rgs16, and Rasl11b. These expressional changes may underlie the phenotype of the Nmu/Nms/Gpr176 knockout mice. Our data argue that there is a mechanism requiring Nmu, Nms, and Gpr176 for the proper modulation of light-induced phase shift in mice. Simultaneous modulation of Nmu/Nms/Gpr176 may provide a potential target option for modulating the circadian clock.

Wetting dynamics of viscoelastic solid films.

We study the wetting phenomena of a soft viscoelastic solid film on a smooth and flat substrate. A poly-dimethylsiloxane (PDMS) rubber film is suspended from a stage at both ends, and the wetting behavior of the film against a glass substrate is observed while lowering the stage at a constant velocity. We find that the dynamics of the rubber-glass-air contact lines vary with the lowering velocity of the stage. When the stage velocity is sufficiently low, the film wets the substrate smoothly and the contact lines are straight throughout. Consequently, the contact line velocity is proportional to the lowering velocity. As the stage velocity is increased, the contact line velocity reaches a maximum at the critical stage velocity and then subsequently decreases. The contact lines are wavy and sensitive to the defects above the critical velocity, resulting in the trapping of air bubbles at the interface. We reproduce the wetting behavior using a simple numerical model, assuming an upper limit for the contact line velocity. The wetting behavior observed in our experiments is attributed to the transition in the in-plane stress state from tensile to compressive along the film, leading to buckling of the film above the critical stage velocity. Our results suggest the existence and importance of the maximum wetting velocity for viscoelastic solids.

Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels.

Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via the calcium (Ca2+)-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through its interaction with VDCCs. The phase-shift magnitude of locomotor activity rhythms by light, at night, increases in Gem-deficient (Gem-/-) mice. Similarly, in SCN slices from Gem-/- mice, depolarizing stimuli induce larger phase shifts of clock gene transcription rhythms that are normalized by the application of an L-type VDCC blocker, nifedipine. Voltage-clamp recordings from SCN neurons reveal that Ca2+ currents through L-type channels increase in Gem-/- mice. Our findings suggest that transcriptionally activated Gem feeds back to suppress excessive light-evoked L-type VDCC activation, adjusting the light-induced phase-shift magnitude to an appropriate level in mammals.

Derivation of Two-Fluid Model Based on Onsager Principle.

Using the Onsager variational principle, we study the dynamic coupling between the stress and the composition in a polymer solution. In the original derivation of the two-fluid model of Doi and Onuki the polymer stress was introduced a priori; therefore, a constitutive equation is required to close the equations. Based on our previous study of viscoelastic fluids with homogeneous composition, we start with a dumbbell model for the polymer, and derive all dynamic equations using the Onsager variational principle.

Gas-liquid transition of van der Waals fluid confined in fluctuating nano-space.

Gas-liquid transition is generally a complex process, which involves nucleation of droplets and their growth by evaporation-condensation or collision-coalescence processes. Here, we focus on a microscopic system in which there is only one liquid droplet at most. In this case, we can develop an equilibrium theory for the formation of the droplet in the gas phase using the classical nucleation theory. We use the van der Waals fluid model with surface tension and calculate the size fluctuation of the droplet for various confinement conditions, NVT (in which the volume V of the system is fixed), NPT (in which the pressure P of the system is fixed), and NBT (in which the system is confined in a nano-bubble immersed in a host liquid, where both V and P can fluctuate). We show that in the NBT system, the size flexibility along with space confinement induces a wealth of properties that are not found in NVT and NPT. It exhibits richer phase behaviors: a stable droplet appears and coexists with the pure gas phase and/or pure liquid phase. When compared to the NVT system, the NBT system shows not only the oscillatory fluctuation between the two stable states but also a large fluctuation in the total volume and the pressure.

Evaporation Dynamics of Sessile Droplets: The Intricate Coupling of Capillary, Evaporation, and Marangoni Flow.

A single-component droplet placed on a completely wetting substrate shows a pseudostable apparent contact angle (θapp) during evaporation. We propose a simple theory to explain the phenomenon accounting for the liquid evaporation and the internal flow induced by the capillary and Marangoni effects. The theory predicts that when evaporation starts, the contact angle approaches to θapp in a short time τs, remains constant for most of the time of evaporation, and finally increases rapidly when the droplet size becomes very small. This explains the behavior observed for alkane droplets. Analytical expressions are given for the apparent contact angle θapp and the relaxation time τs, which predict how they change when the evaporation rate, droplet size, and other experimental parameters such as thermal conductivity of the substrate are changed.

Capillary Rising in a Tube with Corners.

We studied the dynamics of a fluid rising in a capillary tube with corners. In the cornered tube, unlike the circular tube, fluid rises with two parts, the bulk part where the entire cross-section is occupied by the fluid and the finger part where the cross-section is only partially filled. Using the Onsager principle, we derive coupled time-evolution equations for the two parts. We show the following: (a) At the early stage of rising, the dynamics is dominated by the bulk part and the fluid height h0(t) shows the same behavior as that in the circular tube. (b) At the late stage, the bulk part stops rising but the finger part continues, following the scaling law h1(t) ∼ t1/3. We also show that, due to the coupling between the two parts, the equilibrium bulk height is smaller than the Jurin's height, which ignores the effect of the finger part.

[Roles of the Circadian Clock Mechanism in the Regulation of Daily Rhythms of Body Temperature].

Body temperature of thermostatic animals does not stay constant but displays a regular circadian fluctuation, which has a role in maintaining homeostasis of sleep and metabolism as well as entraining the peripheral circadian clocks in the body. Following the discovery of clock genes that generate the circadian rhythm and the master clock structure in the brain and recent advances in infrared temperature imaging, there is a greater opportunity to investigate the mechanism underlying body temperature regulation, which currently remains unclear. In this review, we summarize our recent findings on a mechanism of body temperature regulation through a non-coding cis-element of the core clock gene Per2. The body temperature during siesta is controlled by the calcitonin receptors, which exhibit restricted expression in the suprachiasmatic nucleus, the locus of the central circadian clock in the brain. This review also refers to a recent machine learning-assisted thermography recording procedure, a technique that enables real-time simultaneous monitoring of circadian fluctuations in body temperature, locomotor activity, feeding, and drinking behaviors of animals. We will discuss the current challenges and open questions in understanding the molecular and circuit level mechanisms that give rise to circadian rhythms in body temperature.

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction.

Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3ß-hydroxyl-steroid dehydrogenase (3ß-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3ß-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3ß-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3ß-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction.